Indole derivatives for the treatment of osteoporosis

ABSTRACT

A compound of formula (I), or a salt thereof, or a solvate thereof, wherein Ra represents a group R 5  which is hydrogen, alkyl or optionally substituted aryl and Rb represents a moiety of formula (a), wherein X represents a hydroxy or an alkoxy group wherein the alkyl group may be substitued or unsubstituted or X represents a group NR s R t  wherein R s  and R t  each independently represent hydrogen, alkyl, substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted arylalkyl, an optionally substituted heterocyclic group or an optionally substituted heterocyclylalkyl group, or R s  and R t  together with the nitrogen to which they arm attached form a heterocyclic group; R 1  represents an alkyl or a substituted or unsubstituted aryl group; and R 2 , R 3  and R 4  each independently represent hydrogen, alkyl, aryl or substituted aryl; R 6  and R 7  each independently represent hydrogen, hydroxy, amino, alkoxy, optionally substituted aryloxy, optionally substituted benzyloxy, alkylamino, dialkylamino, halo, trifluoromethyl, trifluoromethoxy, nitro, alkyl, carboxy, carbalkoxy, carbamoyl, alkylcarbamoyl, or R 6  and R 7  together represent methylenedioxy, carbonyldioxy or carbonyldiamino; and R 8  represents hydrogen, hydroxy, alkynoyl, alkyl, aminoalkyl, hydroxyalkyl, carboxyalky, carbalkoxyalkyl, carbamoyl or aminosulphonyl; a process for preparing such a compound, a pharmaceutical composition containing such a compound and the use of such a compound in medecine.

[0001] This invention relates to certain novel compounds, to a processfor preparing such compounds, to pharmaceutical compositions containingsuch compounds and to the use of such compounds and compositions inmedicine.

[0002] Co-pending International Application, application numberPCT/EP96/00157, publication number WO 96/21644, discloses certain indolederivatives of formula (A): formula (I):

[0003] or a salt thereof, or a solvate thereof, wherein

[0004] either: (i) R′a represents a group R′₅ which is hydrogen, alkylor optionally substituted aryl and R′b represents a moiety of formula(a′):

[0005] wherein X′ represents a hydroxy or an alkoxy group wherein thealkyl group may be substituted or unsubstituted or X′ represents a groupNR′_(s)R′_(t) wherein R′_(s) and R′_(t) each independently representhydrogen, alkyl, substituted alkyl, optionally substituted alkenyl,optionally substituted aryl, optionally substituted arylalkyl, anoptionally substituted heterocyclic group or an optionally substitutedheterocyclylalkyl group, or R′_(s) and R′_(t) together with the nitrogento which they are attached form a heterocyclic group; R′₁ represents analkyl or a substituted or unsubstituted aryl group; and R′₂, R′₃ and R′₄each independently represent hydrogen, alkyl, aryl or substituted aryl

[0006] or (ii) R′_(a) represents a moiety of the above defined formula(a) and R′_(b) represents the above defined R′₅;

[0007] R′₆ and R′₇ each independently represents hydrogen, hydroxy,amino, alkoxy, optionally substituted aryloxy, optionally substitutedbenzyloxy, alkylamino, dialkylamino, halo, trifluoromethyl,trifluoromethoxy, nitro, alkyl, carboxy, carbalkoxy, carbamoyl,alkylcarbamoyl, or R′₆ and R′₇ together represent methylenedioxy,carbonyldioxy or carbonyldiamino; and

[0008] R′₈ represents hydrogen, hydroxy, alkanoyl, alkyl, aminoalkyl,hydroxyalkyl, carboxyalkyl, carbalkoxyalkyl, carbamoyl oraminosulphonyl, which compounds are indicated interalia to reduce boneresorption by inhibiting osteoclast H⁺-ATPase.

[0009] Diseases associated with loss of bone mass are known to be causedby over activity of osteoclast cells. It is also known that certaincompounds, usually related to bafilomycin, are useful for treating suchdiseases: For example International Patent Application, publicationnumber WO 91/06296 discloses certain bafilomycin macrolides for thetreatment of bone affecting diseases.

[0010] However, bafilomycin derivatives are not selective forosteoclasts in humans. The use of these compounds is thereforeassociated with unacceptable toxicity due to generalised blockade ofother essential v-ATPases. Indeed, to date there is no known treatmentwhich is selective for the human osteoclasts.

[0011] The search for a successful treatment for diseases associatedwith loss of bone mass in humans is further complicated in that thenature of the therapeutic target for the selective inhibition of theosteoclasts is controversial. Thus Baron et al (International PatentApplication publication number WO93/01280) indicate that a specificvacuolar ATPase (V-ATPase) has been identified in osteoclasts as apotential therapeutic target. However, the Baron work was carried out inchickens and Hall et al (Bone and Mineral 27, 1994, 159-166), in a studyrelating to mammals, conclude that in contrast to avian osteoclastV-ATPase, mammalian osteoclast V-ATPase is pharmacologically similar tothe v-ATPase in other cells and, therefore, it is unlikely to be a goodtherapeutic target.

[0012] We have now found a group of novel compounds from within thescope of WO 96/21644 which are especially selective for mammalianosteoclasts, especially human osteoclasts, acting to selectively inhibittheir bone resorbing activity. These compounds are therefore consideredto be particularly useful for the treatment and/or prophylaxis ofdiseases associated with loss of bone mass, such as osteoporosis andrelated osteopenic diseases, Paget's disease, hyperparathyroidism andrelated diseases. These compounds are also considered to possessanti-tumour activity, antiviral activity (for example against SemlikiForest, Vesicular Stomatitis, Newcastle Disease, Influenza A and B, HIVviruses), antiulcer activity (for example the compounds may be usefulfor the treatment of chronic gastritis and peptic ulcer induced byHelicobacter pylori), immunosupressant activity, antilipidemic activity,antiatherosclerotic activity and to be useful for the treatment of AIDSand Alzheimer's disease. In a further aspect, these compounds are alsoconsidered useful in inhibiting angiogenesis, i.e. the formation of newblood vessels which is observed in various types of pathologicalconditions (angiogenic diseases) such as rheumatoid arthritis, diabeticretinopathy, psoriasis and solid tumours

[0013] Accordingly, in its broadest aspect the the present inventionprovides a selective inhibitor of the biological activity of humanosteoclast cells, in particular the bone resorption activity of humanosteoclast cells associated with abnormal loss of bone mass, providingthat such an inhibitor does not include any specific Example disclosedin WO 96/21644. In a further aspect the invention provides a selectiveinhibitor of the biological activity of human osteoclast cells, inparticular the bone resorption activity of human osteoclast cellsassociated with abnormal loss of bone mass, providing that such aninhibitor does not include a compound of the hereinbefore definedcompound of formula (A). A particular inhibitor of human osteoclastcells is a selective inhibitor of the vacuolar H⁺-ATPase located on theruffled border of human osteoclasts.

[0014] In one particular aspect the selective inhibitor interactsspecifically with the 16 kDa subunit of the vacuolar H⁺-ATPase locatedon the ruffled border of human osteoclasts whose function and structureis similar to other known 16 kDa subunits, for example that reported inP. C. Jones et al., Membrane Dynamics and Transport, 22, 805-809 (1994).

[0015] In a further particular aspect, the selective inhibitor interactsspecifically with the 116 kDa subunit of the vacuolar H+-ATPase locatedon the ruffled border of human osteoclasts (for example the proteinreported in Y-P. Li et al., Biochem. Biophys. Res. Commun, 218, 813-821(1996)).

[0016] In particular, the invention provides a compound of formula (I):

[0017] or a salt thereof, or a solvate thereof, wherein

[0018] Ra represents a group R₅ which is hydrogen, alkyl or optionallysubstituted aryl and Rb represents a moiety of formula (a):

[0019] wherein X represents a hydroxy or an alkoxy group wherein thealkyl group may be substituted or unsubstituted or X represents a groupNR_(s)R_(t) wherein R_(s) and R_(t) each independently representhydrogen, alkyl, substituted alkyl, optionally substituted alkenyl,optionally substituted aryl, optionally substituted arylalkyl, anoptionally substituted heterocyclic group or an optionally substitutedheterocyclylalkyl group, or R_(s) and R_(t) together with the nitrogento which they are attached form a heterocyclic group; R₁ represents analkyl or a substituted or unsubstituted aryl group; and R₂, R₃ and R₄each independently represent hydrogen, alkyl, aryl or substituted aryl

[0020] R₆ and R₇ each independently represents hydrogen, hydroxy, amino,alkoxy, optionally substituted aryloxy, optionally substitutedbenzyloxy, alkylamino, dialkylamino, halo, trifluoromethyl,trifluoromethoxy, nitro, alkyl, carboxy, carbalkoxy, carbamoyl,alkylcarbamoyl, or R₆ and R₇ together represent methylenedioxy,carbonyldioxy or carbonyldiamino; and

[0021] R₈ represents hydrogen, hydroxy, alkanoyl, alkyl, aminoalkyl,hydroxyalkyl, carboxyalkyl, carbalkoxyalkyl, carbamoyl oraminosulphonyl.

[0022] In one aspect R₁ represents alkyl or substituted or unsubstitutedphenyl.

[0023] Suitably R₁ represents alkyl.

[0024] Favourably, R₁ represents a C₁₋₄-alkyl group, for example methylor ethyl

[0025] Preferably, R₁ represents methyl.

[0026] In one aspect, R₂, R₃ and R₄ each independently representhydrogen, alkyl or phenyl.

[0027] Examples of R₂ include hydrogen and methyl.

[0028] Suitably, R₂ represents hydrogen.

[0029] Examples of R₃ include hydrogen and methyl or ethyl.

[0030] Suitably, R₃ represents hydrogen.

[0031] Examples of R₄ include hydrogen, propyl and phenyl, especiallyhydrogen and phenyl.

[0032] Suitably, R₄ represents hydrogen.

[0033] In one aspect, R₅ is hydrogen, alkyl or substituted or, suitably,unsubstituted phenyl.

[0034] Examples of R₅ include hydrogen, ethyl and 4-methoxyphenyl,especially hydrogen and ethyl.

[0035] Suitably, R₅ is hydrogen.

[0036] In one aspect R₆ and R₇ each independently represents hydrogen,hydroxy, amino, alkoxy, optionally substituted phenyloxy, optionallysubstituted benzyloxy, alkylamino, dialkylamino, halo, trifluoromethyl,nitro, alkyl, carboxy, carbalkoxy, carbamoyl, alkylcarbamoyl, or R₆ andR₇ together represent methylenedioxy, carbonyldioxy or carbonyldiamino.

[0037] Suitably, R₆ and R₇ each independently represents alkoxy, halo,trifluoromethyl, nitro, and alkyl.

[0038] When R₆ or R₇ represents alkoxy, said alkoxy group is suitably aC₁₋₆ alkoxy for example methoxy.

[0039] When R₆ or R₇ represents halo, said halo group is suitably afluoro, chloro or bromo group, especially a chloro or bromo group.

[0040] When R₆ or R₇ represents alkyl, said alkyl group is suitably aC₁₋₆ alkyl for a example butyl group.

[0041] Suitable positions for substitution for R₆ or R₇ are the 4, 5, 6or 7 position, favourably the 5 or 6 position.

[0042] When neither of R₆ or R₇ represent hydrogen then favouredpositions for bis-substitution are 5 and 6 positions.

[0043] Favoured values for R₆ and R₇ are hydrogen, halo, trifluoromethyland alkoxy.

[0044] In one aspect R₆ is hydrogen and R₆ or R₇ represents hydrogenalkoxy, halo, nitro, trifluoromethyl and alkyl.

[0045] In a further aspect R₆ and R₇ are each selected from hydrogen,halo and alkoxy, examples include: R₆ is halo and R₇ is halo; R₆ is haloand R₇ is alkyl; R₆ is alkoxy and R₇ is alkoxy.

[0046] In a preferred aspect R₆ is halo, especially 5-halo, and R₇ ishalo, especially 6-halo.

[0047] Most preferably R₆ is chloro, especially 5-chloro, and R₇ ischloro, especially 6-chloro.

[0048] Examples of R₈ include hydrogen, methyl andt-butoxycarbonylmethyl.

[0049] A further example of R₈ is a carboxymethyl group.

[0050] Suitably, R₈ represents hydrogen.

[0051] When X represents an alkoxy group, the alkyl group thereof ispreferably an unsubstituted alkyl group.

[0052] Suitably, X represents the above defined group N R_(s) R_(t).

[0053] In one aspect, R_(s) and R_(t) each independently representhydrogen, alkyl, substituted alkyl, optionally substituted alkenyl,optionally substituted aryl, optionally substituted arylalkyl, anoptionally substituted heterocyclic group or an optionally substitutedheterocyclylalkyl group.

[0054] R_(s) and R_(t) can also each independently represent cycloalkylor substituted cycloalkyl.

[0055] In a further aspect, R_(s) and R_(t) together represent aheterocyclic group.

[0056] When R_(s) or R_(t) represent alkyl or substituted alkyl,suitable alkyl groups are C₁₋₆ alkyl groups, for example C₁, C₂, C₃, C₄and C₅ alkyl groups, favourably ethyl, propyl or butyl.

[0057] When R_(s) or R_(t) represent substituted alkyl, favoured groupsare 2-(dialkylamino)ethyl or 3-(dialkylamino)propyl or4-(dialkylamino)butyl or heterocyclylmethyl or heterocyclylethyl orheterocyclylpropyl groups.

[0058] A further favoured group for R_(s) or R_(t) is heterocyclylalkyl,especially heterocyclyl-C₁₋₆ alkyl, in particular heterocyclyl-(CH₂)₂—or heterocyclyl-(CH₂)₃—.

[0059] One favoured heterocyclyl substituent for alkyl groups, such asheterocyclylmethyl, heterocyclylethyl or heterocyclylpropyl groupsinclude piperazinyl groups.

[0060] Further favoured heterocyclyl substituents for alkyl groups, suchas heterocyclylmethyl, heterocyclylethyl or heterocyclylpropyl groupsinclude homopiperazinyl groups.

[0061] When R_(s) or R_(t) represent cycloalkyl or substitutedcycloalkyl, suitable cycloalkyl groups are C₅₋₉ cycloalkyl groups, forexample a cyclopentyl or cyclohexyl group. When R_(s) or R_(t) representalkenyl or substituted alkenyl, suitable alkenyl groups are C₂₋₆ alkenylgroups, for example a C₅ alkenyl group.

[0062] When R_(s) or R_(t) represent aryl or substituted aryl, suitablearyl groups are phenyl groups.

[0063] In one favoured aspect R_(t) is hydrogen.

[0064] Suitable heterocyclic groups include single ring saturatedheterocyclic groups, single ring unsaturated heterocyclic groups, fusedring heterocyclic groups.

[0065] Fused ring heterocyclic groups include spiro heterocyclic groups.

[0066] Suitable single ring unsaturated heterocyclic groups comprise 5-,6- or 7-membered rings.

[0067] Suitable 5-membered single ring unsaturated heterocyclic groupsare furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, furazanyl, thiazolyl and isothiazolylgroups; or partially saturated derivatives thereof, such as4,5-dihydro-1,3-thiazol-2-yl, 1H-imidazolinyl, pyrrolinyl, pyrazolinyl,oxazolinyl, isoxazolinyl, thiazolinyl groups.

[0068] Suitable 6-membered single ring unsaturated heterocyclic groupsare pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl,1,2- or 1,3- or 1,4-oxazinyl, 1,2- or 1,3- or 1,4-thiazinyl and pyranylgroups, or partially saturated derivatives thereof such as 1,2- or 1,3-or 1,4-dihydrooxazinyl, 1,4-dihydropyridyl, dihydropyridazinyl,dihydropyrazinyl or dihydropyrimidinyl.

[0069] A further suitable 6-membered single ring unsaturatedheterocyclic group is a pyridin-2-one-5-yl group.

[0070] Suitable 7-membered single ring unsaturated heterocyclic groupsare azepinyl, oxepinyl, diazepinyl, thiazepinyl, oxazepinyl or partiallysaturated derivatives thereof.

[0071] Suitable, single ring saturated heterocyclic groups comprise 5-,6- or 7-membered rings.

[0072] Suitable 5-membered single ring saturated heterocyclic groups arepyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,isoxazolidinyl and terahydrofuranyl groups.

[0073] Suitable 6-membered single ring saturated heterocyclic groups arepiperidinyl, piperazinyl, tetrahydropyranyl, 1,3-dioxacyclohexyl,tetrahydro-1,4-thiazinyl, morpholinyl and morpholino groups.

[0074] Suitable piperazinyl groups are 1-piperazinyl groups, especially1-piperazinyl groups substituted in the 4 position with an acyl group,suitably a phenylcarbonyl group, or a heterocyclic group, such as apyrimidyl group, or an optionally substituted phenyl group, such as aphenyl group with 1, 2, or 3 subsitutents selected from alkoxy andhalogen.

[0075] Suitable 7-membered single ring saturated heterocyclic groups arehexamethyleniminyl, oxepanyl and thiepanyl.

[0076] Suitable fused ring heterocyclic groups include fused saturatedrings, fused unsaturated rings and saturated rings fused to unsaturatedrings.

[0077] Preferred fused ring heterocyclic groups include those comprisingtwo or three rings wherein each ring comprises 4 to 8 ring atomsincluding 1, 2 or 3, especially 1 or 2, hetero atoms.

[0078] Suitable hetero atoms are nitrogen atoms.

[0079] Suitable groups having fused saturated rings are polycyclicgroups wherein the rings share a single atom, one bond or more than onebond, for example 2 bonds or three bonds. Suitable groups having fusedsaturated rings are quinuclidyl, 8-azabicyclo[3.2.1]octyl,9-azabicyclo[3.3.1]nonyl, 1-azabicyclo[3.3.3]undecyl,1,9-diazabicyclo[3.3.1] and 1,5-diazabicyclo[3.3.1]nonyl groups.

[0080] Further suitable groups having fused saturated rings aredecahydro-pyrrolo[2.1.5-cd]indolizinyl, octahydroindolizinyl,octahydro-2H-quinolizinyl and tricyclo[3.3.1.1^(3,7)]decyl groups.

[0081] A further suitable group comprising a fused saturated ring is anonyl 1-azabicyclo[3.3.1]nonyl, 3,7-diazabicyclo[3.3.1]nonyl group.

[0082] Suitable groups having fused unsaturated rings arepyrazo[3.4-d]pyrimidinyl, 1,2,5-thiadiazolo[3,4-b]pyridyl,isoxazolo[4,5-b]pyridyl, thiazolo[4,5-b]pyridyl,oxazolo[4,5-d]pyrimidinyl, 7H-purin-2-yl, quinolyl, isoquinolyl,benzo[b]thienyl, benzofuranyl, isobenzofuranyl, benzoxazolyl,benzothiazolyl, indolizinyl, indolyl, isoindolyl, indazolyl,phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl,pteridinyl and β-carbolinyl groups.

[0083] Suitable groups having saturated rings fused to unsaturated ringsincludes groups which are fused to benzene rings such astetrahydroquinolyl, 4H-quinolizinyl, tetrahydroisoquinolyl,dihydrobenzofuryl, chromenyl, chromanyl, isochromanyl, indolinyl andisoindolinyl groups.

[0084] Suitable spiro heterocyclic groups include oxaspiro[4.5]decyl,azaspiro[4.5]decyl, 1,2,4-triazaspiro[5.5]undecyl,1,4-dioxa-9-azaspiro[4.7]dodecyl and 1-azaspiro[5.5]undecyl.

[0085] Suitable values for R_(s) include hydrogen, C₁₋₅ alkyl, mono- di-and tri-hydroxyalkyl, alkoxyalkyl, carboxyalkyl, carbalkoxyalkyl,bisphosphonylalkyl, (substituted)amino-carboxyalkyl,biscarbethoxy-hydroxyalkenyl, dialkylaminoalkylpyridyl, mono- di- andtri-alkoxypyridyl, dialkylaminoalkoxypyridyl, aryloxypyridyl,aminopyridyl, substituted piperazinyl, quinuclidyl, saturatedheterocyclylalkyl, substituted piperidinyl, (di)azabicycloalkyl,substituted phenyl, substituted benzyl, substituted phenylethyl,1-imidazolylalkyl, thiazolinyl, (2-tetrahydroisoquinolinyl)alkyl,1H-pyrazolo[3,4-d]pyrimidin-4-yl, 7H-purin-2-yl, pyridylalkyl,(2-pyrimidinyl)piperazin-1-ylalkyl, substituted pyridazinyl, substitutedpyrazinyl, substituted pyrimidinyl, quinolyl, isoquinolyl,tetrahydroisoquinolyl, tetrahydroquinolyl.

[0086] Other suitable valuse for Rs include,(4-substituted)piperazinoalkyl and aminopyrimidiniyl.

[0087] Preferred values for R_(s) include diethylaminopropyl,3-amino-3-carboxypropyl, 4-amino-4-carboxybutyl, 3-pyridyl,diethylaminoethyl, 3-quinuclidyl (or 1-azabicyclo[2.2.2]octan-3-yl),morpholinopropyl, piperidinopropyl, 1-methyl-2-pyrrolidinylethyl,2,2,6,6-tetramethyl-4-piperidinyl, 2-methoxy-5-pyridyl,2-methylpiperidinopropyl, 8-methyl-8-azabicyclo[3.2.1]oct-3β-yl,1-methyl-4-piperidinyl, 1H-pyrazolo[3,4-d]pyrimidin-4-yl,2,2,5,5-tetramethyl-3-pyrrolidinylmethyl, 2-methoxy-4-pyridyl,1-ethyl-3-piperidinyl, 3-[4-(2-pyrimidinyl)piperazin-1-yl]propyl.

[0088] Other preferred values for R_(s) include dimethylaminopropyl,dibutylaminopropyl, 2-methoxy-pyrimidin-5-yl,3-[4-(3-chlorophenyl)piperazin-1-yl]propyl,3-[4-(2-phenyl)piperazin-1-yl]propyl,3-[2,6-dimethyl-4-(2-pyrimidinyl)piperazin-1-yl]propyl],3-dimethylamino-cyclohexyl,1-(2-hydroxyethyl)-2,6-dimethylpiperidin-4-yl, 8aβH-5α-methyl-octahydroindolizin-7α-yl,3-[4-(2-pyridyl)piperazin-1-yl]propyl,3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl and3-[4-(2-pyrimidinyl)homopiperazin-1-yl]propyl].

[0089] Other preferred values for R_(s) include1,2,2,6,6-pentamethyl-4-piperidinyl, 1,2,6-trimethyl-4-piperidinyl and1,2,2,6-tetramethyl-4-piperidinyl groups.

[0090] Suitable values for R_(t) include hydrogen, methyl, C₂₋₅ alkyl,2-hydroxyethyl, 2-methoxyethyl, carboxymethyl, carbomethoxymethyl,4-hydroxybutyl and 2,3-dihydroxypropyl, especially hydrogen.

[0091] In one preferred aspect R_(t) represents hydrogen.

[0092] A particular 6 membered single ring unsaturated heterocyclicgroup is a moiety of formula (H1):

[0093] wherein Z₁ is N or CX₅ wherein X₅ is selected from hydrogen,alkyl, alkoxy, alkylcarbonyl, aryl, aryloxy or arylcarbonyl and Z₂, X₃and X₄ are each independently selected from hydrogen, alkyl, aryl,cyano, amino, heterocyclyloxy, alkoxy carbonylalkyloxy, carboxyalkyloxy,aminoalkyloxy, aminoalkylamino, aminoalkenylamino (especiallyaminomethyleneamino) and alkanoylamino.

[0094] A particularly preferred compound of the invention is a compoundof formula (I) wherein: R_(a) is a group R₅ wherein R₅ is as defined inrelation to formula (I); R_(b) is a moiety of formula (a) wherein R₁,R₂, R₃ and R₄ are as defined in relation to formula (I) and X is amoiety NR_(s)R_(t) wherein R_(s) is a group (H1) as defined above, andR_(t) is hydrogen.

[0095] A favoured moiety NR_(s)R_(t) is an optionally substitutedpiperidinyl group, especially wherein one of the substituents is anN-alkyl group.

[0096] Particular substituents for piperidinyl groups are alkyl groups,especially when attached to one or, favourably, both of the carbon atomsalpha to the ring nitrogen atom.

[0097] Piperidinyl groups of especial interest are those wherein one or,favourably, both of the carbon atoms alpha to the ring nitrogen atom aresubstitued with one or, favourably, two alkyl groups.

[0098] Further particular substituents for piperidinyl groups arealkylene groups, especially when attached to one, favourably both, ofthe carbon atoms alpha to the ring nitrogen atom.

[0099] A particular 6 membered, saturated heterocyclic group is a groupof formula (H2):

[0100] wherein X₆, X₇, X₈, X₉, X₁₀, X₁₁, X₁₂ and X₁₃ are eachindependently selected from hydrogen, hydroxy, alkyl, suitably C₁₋₆alkyl, cycloalkyl (including spirocondensed), mono or poly hydroxyalkyl,alkoxyalkyl, hydroxy-alkoxyalkyl, alkanoyl, alkoxycarbonyl, aminoalkyl(optionally alkylated or acylated at nitrogen);

[0101] or one of X₆ with X₁₂ and X₈ with X₁₀ represents a C₂₋₄ alkylenechain and the remaining variables X₇, X₁₃, X₉ and X₁₁ each independentlyrepresent hydrogen, hydroxy, alkyl, suitably C₁₋₆ alkyl, cycloalkyl(including spirocondensed), mono or poly hydroxyalkyl, alkoxyalkyl,hydroxy-alkoxyalkyl, alkanoyl, alkoxycarbonyl, aminoalkyl (optionallyalkylated or acylated at nitrogen); and X₁₄ represents hydrogen oralkyl, especially C₁₋₆ alkyl, mono or polyhydroxyalkyl, mono ordiaminoalkyl, aminocarbonyl, alkylcarboxyalkyl, carbalkoxyalkyl, aryl,heterocyclyl, acyl, carbamoyl, alkylamino(cyanimidoyl), aminoalkanoyl,hydroxyalkanoyl.

[0102] Suitably, X₆, X₇, X₁₂ and X₁₃ each represent hydrogen.

[0103] Suitably, X₈, and X₉ each independently represent hydrogen oralkyl, especially alkyl, for example methyl.

[0104] Suitably, X₁₀ and X₁₁ each independently represent hydrogen oralkyl, especially alkyl, for example methyl

[0105] Suitably, X₁₄ represents alkyl, for example methyl

[0106] In one preferred aspect X₈, X₉, X₁₀ and X₁₁ each independentlyrepresent alkyl, especially methyl, and X₆, X₇, X₁₂ and X₁₃ eachrepresent hydrogen.

[0107] In a most preferred aspect X₈, X₉, X₁₀ and X₁₁ each independentlyrepresent alkyl, especially methyl, and X₆, X₇, X₁₂ and X₁₃ eachrepresent hydrogen and X₁₄ represents alkyl, especially methyl.

[0108] A preferred compound of the invention is a compound of formula(I) wherein R_(a) is a group R₅ wherein R₅ is as defined in relation toformula (I); R_(b) is a moiety of formula (a) wherein R₁, R₂, R₃ and R₄are as defined in relation to formula (I) and X is a moiety NR_(s)R_(t)wherein R_(s) is a moiety of formula (f) defined below, especially amoiety (f) wherein k is zero and H₀ is a moiety (a) as defined below, ora moiety (H1) or (H2) as defined above, and R_(t) is hydrogen, suitablywherein R_(s) is a moiety of formula (H1) or (H2) and R₆, R₇ and R₈ areas defined in relation to formula (I).

[0109] A particularly preferred compound of the invention is a compoundat formula (I) wherein R_(a) is a group R₅ wherein R₅ is as defined inrelation to formula (I); R_(b) is a moiety of formula (a) wherein R₁,R₂, R₃ and R₄ are as defined in relation to formula (I) and X is amoiety NR_(s)R_(t) wherein R_(s) is a group (H2), as defined above, andR_(t) is hydrogen and R₆, R₇ and R₈ are as defined in relation toformula (I).

[0110] Of particular mention are the compounds wherein R₁ is C₁₋₆ alkyl,especially methyl, R₂, R₃, R₄ and R₈ are hydrogen, R₆ is 5-halo,especially 5-chloro, R₇ is 6-halo, especially 6-chloro, and X is amoiety NR_(s)R_(t) wherein R_(t) is hydrogen and R_(s) is a moiety offormula (f) defined below or a moiety (H1) or (H2) as defined above,suitably wherein R_(s) is a moiety of formula (H1) or (H2).

[0111] Of particular mention are the compounds wherein R₁ is C₁₋₆ alkyl,especially methyl, R₂, R₃, R₄ and R₈ are hydrogen, R₆ is 5-halo,especially 5-chloro, R₇ is 6-halo, especially 6-chloro, and X is amoiety NR_(s)R_(t) wherein R_(t) is hydrogen and Rs is a moiety (f),especially a moiety (f) wherein k is zero and H₀ is a moiety (a).

[0112] Of particular mention are the compounds wherein R₁ is C₁₋₆ alkyl,especially methyl, R₂, R₃, R₄ and R₈ are hydrogen, R₆ is 5-halo,especially 5-chloro, R₇ is 6-halo, especially 6-chloro, and X is amoiety NR_(s)R_(t) wherein R_(t) is hydrogen and Rs is a moiety (H1).

[0113] Of particular mention are the compounds wherein R₁ is C₁₋₆ alkyl,especially methyl, R₂, R₃, R₄ and R₈ are hydrogen, R₆ is 5-halo,especially 5-chloro, R₇ is 6-halo, especially 6-chloro, and X is amoiety NR_(s)R_(t) wherein R_(t) is hydrogen and Rs is a moiety (H2).

[0114] Particular examples of the invention are the compounds of examplenumbers 1, 31, 32 34, 35, 47, 48, 51, 55, 56, 59, 61, 62, 63, 68, 74 and75.

[0115] Most particularly should be mentioned the compounds of examplenumbers 1, 55, 62, 68, 74 and 75.

[0116] The present invention does not encompass the examples per se ofabove mentioned co-pending International Application, application numberPCT/EP96/0015 publication number WO 96/21644. Thus each of the examplesof WO 96/21644 numbered 1 to 104 and each of the examples disclosed onpage 50 are excluded from the present invention. Thus the inventionexcludes Examples 49, 51, 53, 59, 67, 69, 83, 84, 97 and 100 of WO96/21644. Also, the invention excludes examples 33, 44, 48, 57, 65, 73,91, 95, 98, 99, 101 and 10 of WO 96/21644. In addition the inventionexcludes examples 47, 56, 66 and 70 of WO 96/21644.

[0117] As used herein, the term “alkyl” includes straight or branchedchain alkyl groups having from 1 to 12, suitably 1 to 6, preferably 1 to4, carbon atoms, such as methyl, ethyl, n- and iso-propyl and n- iso-,tert-butyl and pentyl groups, and also includes such alkyl groups whenforming part of other groups such as alkoxy or alkanoyl groups.

[0118] Suitable optional substituents for any alkyl group includehydroxy; alkoxy; a group of formula NR_(u)R_(v) wherein R_(u) and R_(v)each independently represent hydrogen, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted arylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, carboxy, carboxyalkyl, oralkoxycarbonyl, nitro, or R_(u) and R_(v) together with the nitrogen towhich they are attached form an optionally substituted heterocyclicring; carboxy; alkoxycarbonyl; alkoxycarbonylalkyl; alkylcarbonyloxy;alkylcarbonyl; mono- and di-alkylphosphonate; optionally substitutedaryl; and optionally substituted heterocyclyl.

[0119] A preferred alkyl substituent is NR_(u)R_(v), wherein R_(u) andR_(v) each independently represent hydrogen, optionally substitutedaryl, optionally substituted arylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl or R_(u) andR_(v) together with the nitrogen to which they are attached form anoptionally substituted heterocyclic ring.

[0120] When R_(s) or R_(t) represents substituted alkyl, especially C₁₋₄alkyl, particular substituent values are the moieties of formulae (a),(b), (c), (d) and (e):

[0121] wherein A represents a bond or alkylene, suitably C₁₋₃ alkylene,A₁ is alkylene, suitably C₁₋₄ alkylene, and R_(a), R_(b), R_(c), R_(d),R_(e), R_(f) and R_(g) each independently represent hydrogen, alkyl,optionally substituted aryl or an optionally substituted heterocyclicgroupand R_(u) and R_(v) are as defined above.

[0122] One suitable alkyl substituent value is moiety (a).

[0123] One suitable alkyl substituent value is moiety (b).

[0124] One suitable alkyl substituent value is moiety (c).

[0125] One suitable alkyl substituent value is moiety (d).

[0126] One suitable alkyl substituent value is moiety (e).

[0127] In moiety (a), one preferred value for NR_(u)R_(v) is a1-piperazinyl group, preferably substituted in the 4 position with anacyl group, suitably a phenylcarbonyl group, or a heterocyclic group,such as a pyrimidyl group, or an optionally substituted phenyl group,such as a phenyl group with 1, 2 or 3 subsitutents selected from alkoxy,alkyl, trifluoromethyl, and halogen, for example chlorine and methoxy.

[0128] Thus one preferred value of R_(s) or R_(t) is a moiety of formula(f):

—(CH₂)_(k)—(H₀)  (f)

[0129] wherein k is zero and H₀ is a moiety (a) or k is an integer 2 or3 and H₀ is a moiety (b), (c), (d) and (e).

[0130] Preferably in moiety (f), k is zero and H₀ is a moiety (a).

[0131] As used herein, the term “alkenyl” includes straight or branchedchain alkenyl groups having from 2 to 12, suitably 2 to 6 carbon andalso includes such groups when forming part of other groups, an exampleis a butenyl group, such as a 2-butenyl group.

[0132] Suitable optional substituents for any alkenyl group includes thealkyl substituents mentioned above.

[0133] As used herein, the term “aryl” includes phenyl and naphthyl,especially phenyl.

[0134] Suitable optional substituents for any aryl group include up to 5substituents, suitably up to 3 substituents, selected from alkyl,substituted alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, acetyl,cyano, nitro, amino, mono- and di-alkylamino and alkylcarbonylamino.

[0135] Preferred optional substituents for any aryl group are selectedfrom isobutyl, hydroxy, methoxy, phenoxy, diethylaminoethoxy,pyrrolidinoethoxy, carboxymethoxy, pyridyloxy, fluoro, chloro, amino,dimethylamino, aminomethyl, morpholino, bis(carbethoxy)hydroxymethyl,

[0136] Suitable arylalkyl groups include aryl-C₁₋₃-alkyl groups such asphenylethyl and benzyl groups, especially benzyl.

[0137] Preferably, substituted aralkyl groups are substituted in thearyl moiety.

[0138] As used herein, the terms “heterocyclyl” or “heterocyclic”include saturated or unsaturated single or fused, ring heterocyclicgroups, each ring having 4 to 11 ring atoms, especially 5 to 8,preferably 5, 6 or 7 which ring atoms include 1, 2 or 3 heteroatomsselected from O, S, or N.

[0139] As used herein ‘fused ring heterocyclic group’ includespolycyclic heterocyclic groups which share a single atom, such as aspiro ring system, one bond, as in an octahydroindolizinyl group, ormore than one bond, as in an azabicyclo[3.2.1]oct-3-alpha-yl group.

[0140] Suitable optional substituents for any heterocyclyl orheterocyclic group include up to 5 substituents, suitably up to 3substituents, selected from alkyl, substituted alkyl, alkoxy, hydroxy,halo, amino, mono- or di-alkyl amino, alkoxycarbonyl, hydroxyalkyl,alkoxyalkyl, hydroxyalkoxyalkyl, alkoxyalkyloxyalkyl, aryl, aryloxy andheterocyclyl.

[0141] Preferred optional substituents for any heterocyclyl orheterocyclic group are selected from isobutyl, hydroxy, methoxy,phenoxy, diethylaminoethoxy, pyrrolidinoethoxy, carboxymethoxy,pyridyloxy, fluoro, chloro, amino, dimethylamino, aminomethyl,morpholino, bis(carbethoxy)hydroxymethyl.

[0142] Further optional substituents for any heterocyclyl orheterocyclic group include up to 5, suitably up to 3, substituentsselected from the list consisting of: isopropyl, cyano, oxo,arylcarbonyl, heterocyclyloxy, alkoxyalkoxy, alkoxycarbonylalkyloxy,carboxyalkyloxy, aminoalkyloxy, aminoalkylamino, aminoalkenylamino(especially aminomethyleneamino), alkanoylamino, alkoxyamino, aryl,acetamido, 2-(dimethylamino)ethylamino, 2-methoxyethoxy,3-carboxyprop-2-oxy and 2-pyrazinyl.

[0143] Additional optional substituents for any hetrocyclyl orheterocyclic group include up to 5, suitably up to 3, substituentsselected from the list consisting of: carbonylaminoalkyl,aminocarbonylalkyl and alkylcarbonylaminoalkyl.

[0144] For the avoidance of doubt a reference herein to “heterocyclic”includes a reference to “heterocyclyl”.

[0145] As used herein, the term “halo” includes fluoro, chloro, bromoand iodo, suitably fluoro and chloro, favourably chloro.

[0146] Certain of the carbon atoms of the compounds of formula (I)—suchas those compounds wherein R₁-R₈ contains chiral alkyl chains are chiralcarbon atoms and may therefore provide stereoisomers of the compound offormula (I). The invention extends to all stereoisomeric forms of thecompounds of formula (I) including enantiomers and mixtures thereof,including racemates. The different stereoisomeric forms may be separatedor resolved one from the other by conventional methods or any givenisomer may be obtained by conventional stereospecific or asymmetricsyntheses.

[0147] The compounds of formula (I) also possess two double bonds andhence can exist in one or more geometric isomers. The invention extendsto all such isomeric forms of the compounds of formula (I) includingmixtures thereof. The different isomeric forms may be separated one fromthe other by conventional methods or any given isomer may be obtained byconventional synthetic methods. Suitable salts of the compounds of theformula (I) are pharmaceutically acceptable salts. A preferred isomer isthe 2Z, 4E isomer.

[0148] Certain of the compounds herein can exist in various tautomericforms, for example when hydroxy is a substituent on an aryl orheteroaryl ring; it is to be understood that the invention encompassesall such tautomeric forms.

[0149] Suitable pharmaceutically acceptable salts include acid additionsalts and salts of carboxy groups.

[0150] Suitable pharmaceutically acceptable acid addition salts includesalts with inorganic acids such, for example, as hydrochloric acid,hydrobromic acid, orthophosphoric acid or sulphuric acid, or withorganic acids such, for example as methanesulphonic acid,toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citricacid, fumaric acid, malic acid, succinic acid, salicylic acid, maleicacid, glycerophosphoric acid or acetylsalicylic acid.

[0151] Suitable pharmaceutically acceptable salts of carboxy groupsinclude metal salts, such as for example aluminium, alkali metal saltssuch as sodium or potassium and lithium, alkaline earth metal salts suchas calcium or magnesium and ammonium or substituted ammonium salts, forexample those with C₁₋₆ alkylamines such as triethylamine, hydroxy-C₁₋₆alkylamines such as 2-hydroxyethylamine, bis(2-hydroxyethyl)-amine ortri-(2-hydroxyethyl)amine, cycloalkylamines such as dicyclohexylamine,or with procaine, 1,4-dibenzylpiperidine, N-benzyl-β-phenethylamine,dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine,N-methylglucamine or bases of the pyridine type such as pyridine,collidine or quinoline.

[0152] Suitable solvates of the compounds of the formula (I) arepharmaceutically acceptable solvates, such as hydrates.

[0153] The salts and/or solvates of the compounds of the formula (I)which are not pharmaceutically acceptable may be useful as intermediatesin the preparation of pharmaceutically acceptable salts and/or solvatesof compounds of formula (I) or the compounds of the formula (I)themselves, and as such form another aspect of the present invention.

[0154] A compound of formula (I) or a salt thereof or a solvate thereof,may be prepared.

[0155] (a) for compounds of formula (I) wherein Ra represents hydrogen,alkyl or optionally substituted aryl and R_(b) represents a moiety ofthe above defined formula (a), by reacting a compound of formula (II):

[0156] wherein R₂, R₃, R₄, R₆, R₇ and R₈ are as defined in relation toformula (I), with a reagent capable of converting a moiety of formula

[0157]  into a moiety of the above defined formula (a); or

[0158] (b) for compounds of formula (I) where R_(a) represents a moietyof the above defined formula (a) and R_(b) represents hydrogen, alkyl oroptionally substituted aryl, by treating a compound of formula (III):

[0159] wherein R₄, R₆, R₇ and R₈ are as defined in relation to formula(I) with a compound of formula (IV):

[0160] wherein R₁, R₂, R₃ and X are as defined in relation to thecompounds of formula (I) and R₉ is a C₁₋₄ alkyl group; and thereafter,as necessary, carrying out one or more of the following reactions:

[0161] (i) converting one compound of formula (I) into another compoundof formula (I);

[0162] (ii) removing any protecting group;

[0163] (iii) preparing a salt or a solvate of the compound so formed.

[0164] In reaction (a) above, a suitable reagent capable of converting amoiety of the above defined formula

[0165] into a moiety of the above defined formula (a), includesconventional reagents used to convert C═O bonds into carbon carbondouble bonds, such as Wittig or Horner-Emmons reagents, for examplethose of formula (V):

[0166] wherein R₁ is as defined in relation to the compounds of formula(I), X₁ represents X as defined in relation to formula (I) or a groupconvertible thereto and X₂ represents a moiety (R₉O)₂P(O)— wherein R₉ isas defined above or a group Ph₃P—.

[0167] The reaction between the compounds of formula (II) and thereagent capable of converting the group of formula

[0168] into the moiety of formula (a), may be carried out under theappropriate conventional conditions, depending upon the particularreagent chosen, for example:

[0169] When the reagent is a compound of formula (V) wherein X₂ is amoiety (R₉O)₂P(O)—, then the reaction is carried out under conventionalHorner-Emmons conditions, using any suitable, aprotic solvent forexample an aromatic hydrocarbon such as benzene, toluene or xylene, DMF,DMSO, chloroform, dioxane, dichloromethane, preferably, THF,acetonitrile, N-methylpyrrolidone, and the like or mixtures thereof,preferably an anhydrous solvent, at a temperature providing a suitablerate of formation of the required product, conveniently at ambienttemperature or at an elevated temperature, such as a temperature in therange of from 30° C. to 120° C.; preferably the reaction is conducted inthe presence of a base.

[0170] Suitable bases for use in the last above mentioned reactioninclude organic bases, such as butyl lithium, lithium diisopropylamide(LDA), N,N-diisopropylethylamine, 1,5-diazabicyclo[4.3.0]-5-nonene(DBN), 1,5-diazabicyclo[5.4.0]-5-undecene (DBU),1,5-diazabicyclo[2.2.2]octane (DABCO), and inorganic bases, such assodium hydride; preferably sodium hydride, and generally the reaction iscarried out in an inert atmosphere such as nitrogen.

[0171] When the reagent is a compound of formula (V) wherein X₂ is amoiety Ph₃P—, then the reaction is carried out under conventional Wittigconditions. Usually, the reaction is carried out in the presence of abase, in any suitable aprotic solvent. Suitable bases are organic basessuch as triethylamine, trimethylamine, N,N-diisopropylethylamine(DIPEA), pyridine, N,N-dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]-5-nonene (DBN),1,5-diazabicyclo[5.4.0]-5-undecene (DBU), 1,5-diazabicyclo[2.2.2]octane(DABCO) and inorganic bases such as sodium hydride, caesium carbonate,potassium carbonate, preferably sodium hydride. Suitable solvents areconventional solvents for use in this type of reaction, such as aromatichydrocarbons such as benzene, toluene or xylene or the like; DMF, DMSO,chloroform, dioxane, dichloromethane, THF, ethyl acetate, acetonitrile,N-methylpyrrolidone or mixtures thereof, preferably dichloromethane.This reaction is carried out at any temperature providing a suitablerate of formation of the required product, conveniently at ambienttemperature or at an elevated temperature, such as a temperature in therange of from −20° C. to 140° C., preferably in the range of from aboutroom temperature to the reflux temperature of the solvent.

[0172] The reaction between the compounds of formula (III) and theHorner Emmons reagent of formula (IV) may be carried out underconventional Horner Emmons conditions such as those described above.

[0173] A compound of formula (II) may be prepared according to thereaction sequences shown in Schemes (Ia-c) below

[0174] wherein, subject to any qualification mentioned below, R_(a), R₂,R₃, R₄, R₆, R₇ and R₈ are as defined in relation to the compounds offormula (I).

[0175] Compounds of formula (II) may be prepared using either Wittig orHorner-Emmons reactions of keto derivatives of formula (VIII) with theappropriate phosphonium salt or phosphonate using the reactionconditions which are known in the art and described, for example in “TheWittig Reaction”, R. Adams Ed., Vol. 14, p. 270 (1965) or in Angew.Chem. Int. Ed. Engl., 4, 645 (1965).

[0176] When R₂ is other than —H, e.g. alkyl, a compound of formula (II)is obtained directly from a compound of formula (VIII) by Wittig orHorner-Emmons reaction with the appropriate phosphonium salts orphosphonates according to Scheme (Ia).

[0177] When a compound of formula (VIII) is reacted with the abovementioned phosphonates using the Horner-Emmons reaction, theexperimental conditions used are conventional conditions such as thosereported, in Tetrahedron Lett. 1981, 461; Can. J. Chem., 55, 562 (1977);J. Am. Chem. Soc., 102, 1390 (1980); J. Org. Chem., 44, 719 (1979);Synthesis, 1982, 391; and Tetrahedron Lett. 1982, 2183.

[0178] The reaction of compounds of formula (VIII) with the abovementioned phosphonium salts are carried out in the presence of a base inany suitable solvent. Suitable bases include organic bases, such astriethylamine, trimethylamine, N,N-diisopropylethylamine (DIPEA),pyridine, N,N-dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]-5-nonene (DBN),1,5-diazabicyclo[5.4.0]-5-undecene (DBU), 1,5-diazabicyclo[2.2.2]octane(DABCO) and inorganic bases, such as sodium hydride, caesium carbonate,potassium carbonate. Suitable solvents include conventionally usedsolvents, for example aromatic hydrocarbons such as benzene, toluene orxylene or the like; DMF, DMSO, chloroform, dioxane, dichloromethane,THF, ethyl acetate, acetonitrile, N-methylpyrrolidone and the like ormixtures thereof. Preferably, the reaction is carried out at a reactiontemperature of in the range of about −20° C. to 140° C., preferablyabout room temperature to the reflux temperature of the solvent.

[0179] The reaction of compounds of formula (VIII) with phosphonates arecarried out under conventional Horner-Emmons conditions, using anysuitable, aprotic solvent for example an aromatic hydrocarbon such asbenzene, toluene or xylene, DMF, DMSO, chloroform, dioxane,dichloromethane, preferably, THF, acetonitrile, N-methylpyrrolidone, andthe like or mixtures thereof, preferably an anhydrous solvent, at atemperature providing a suitable rate of formation of the requiredproduct, conveniently at ambient temperature or at an elevatedtemperature, such as a temperature in the range of from 30° C. to 120°C.; preferably the reaction is conducted in the presence of a base.

[0180] Suitable bases for use in the last above mentioned reactioninclude organic bases, such as butyl lithium, lithium diisopropylamide(LDA), N,N-diisopropylethylamine, 1,5-diazabicyclo[4.3.0]-5-nonene(DBN), 1,5-diazabicyclo[5.4.0]-5-undecene (DBU),1,5-diazabicyclo[2.2.2]octane (DABCO), and inorganic bases, such assodium hydride; preferably sodium hydride, and generally the reaction iscarried out in an inert atmosphere such as nitrogen.

[0181] When R₂═H, aldehyde (VII) is reacted with aliphatic aldehydes offormula (VI) in presence of bases such as sodium or potassium hydroxideaffording compound (II) as in Scheme (Ib), using the appropriateconventional procedure

[0182] In a further aspect, when R₂═H, a compound of formula (VIII) isreacted with a substituted carbethoxymethylphosphonium salt orcarbethoxymethylphosphonate (Scheme (Ic)), the carboxylic ester obtained(XIV) is then converted into the corresponding alcohol with a reducingagent, suitably a complex metal reducing agent such as lithium aluminiumhydride (LiAlH₄), diisobutyl aluminium hydride (DIBAH) or lithiumborohydride (LiBH₄), in any suitable aprotic solvent for examplemethylene dichloride, chloroform, dioxane, diethyl ether or THF, at anytemperature providing a suitable rate of formation of the requiredproduct, such as a temperature in the range of from −30° C. to 60° C.,for example at room temperature. Then, the intermediate alcohol isoxidised to aldehyde (II) with an oxidising agent such as manganesedioxide, periodinane (Dess-Martin reagent), pyridinium chlorochromate(PCC) or pyridinium dichromate (PDC) or a combination of oxalyl chlorideand DMSO (Swern reaction), preferably manganese dioxide in methylenedichloride.

[0183] A compound of formula (IV) may be prepared according to thereaction sequence shown in Scheme (II) below.

[0184] wherein, subject to any qualification mentioned below, R₁, R₂ andR₃ are as defined in relation to formula (I), R₉ is as defined inrelation to formula (IV) and X₁ is as defined in relation to formula(V).

[0185] Compounds of formula (X) are prepared by reaction of, preferablyanhydrous, chloroaldehydes or chloroketones of formula (IX) withsuitable phosphonium compounds using the appropriate conventionalprocedure as described above for the Wittig reaction; conversion ofintermediate compound (X) into the desired compound (IV) may be effectedby reaction with a suitable trialkylphosphite (R₉O)₃P wherein R₉ is asdefined above, and the reaction is performed in any conventionally usedsolvent, preferably the trialkyl phosphite, and at a suitable reactiontemperature, preferably at the boiling point of the solvent. For examplefrom Scheme (II): the chloroacetaldehyde (IX) was treated with methyl2-methoxy-2-(triphenylphosphonium)acetate bromide in the presence ofDIPEA in chloroform and the intermediate (X) so obtained was convertedinto compound (IV) by refluxing in trimethyl phosphite.

[0186] The compounds of formula (V) can be prepared according to thereaction sequence shown in Scheme (III) below:

[0187] wherein, subject to any qualification mentioned below, R₁ and R₉are as defined in relation to formula (I) and X₁ is as defined inrelation to formula (V).

[0188] The starting material is an α-alkoxycarboxylic ester of formula(XI) which is commercially available or which is prepared according tothe methods known in the art, for example those reported in Rodd'sChemistry of Organic Compounds, Vol ID, p. 96 (1965), S. Coffey Ed.,Elseviers. The compound of formula (XI) is reacted with an N-haloimide,for example N-bromosuccinimide in the presence of a radical producingagent such as azobisisobutyrronitrile or benzoyl peroxide in a suitablesolvent such as carbon tetrachloride, benzene, for example carbontetrachloride and at a reaction temperature in the range of from

[0189] −30° C. and 80° C., for example at room temperature; examples ofsuch a reaction may be found in the literature, for example J. Org.Chem., 41, 2846 (1976). The halocompound obtained, of formula (XII), isthen reacted either with triphenylphosphine or with a trialkyl phosphiteP(OR₉)₃ to give the required compound of formula (V) as shown in scheme(III).

[0190] When the compound of formula (XII) is reacted withtriphenylphosphine, the reaction is performed in any conventionally usedsolvent, for example diethyl ether, dioxane, tetrahydrofuran, benzene,xylene or, preferably, toluene at a suitable reaction temperature in therange of from −30° C. to 80° C., for example at room temperature(examples of this conversion are reported in the literature, for examplein Chem. Ber., 97, 1713 (1964)).

[0191] When the compound of formula (XII) is reacted with trialkylphosphite P(OR₉)₃, the reaction is performed in any conventionally usedsolvent, preferably the trialkyl phosphite, and at a suitable reactiontemperature, preferably at the boiling point of the solvent (examples ofthis conversion are reported in the literature, for example in LiebigsAnn. Chem., 699, 53 (1966)).

[0192] Alternatively, a compound of formula (V) in which R₂ is (R₉O)₂POmay be prepared using the procedure depicted in Scheme (III), byreacting a diazophosphonoacetates of formula (XIII) with an alcohol orphenol of formula R₁OH, wherein R₁ is as defined in relation to formula(I), in the presence of rhodium (II) acetate as described in theliterature, for example in Tetrahedron, 50, 3177 (1994) or inTetrahedron, 48, 3991 (1992).

[0193] The compounds of formula (III), (VII) and (VIII), are knowncompounds or they are prepared using methods analogous to those used toprepare known compounds, such as those described in J. Org. Chem., 47,757 (1982); Heterocycles, 22, 1211 (1984); Tetrahedron, 44, 443 (1988),Liebigs Ann. Chem., 1986, 438; Chem. Pharm. Bull., 20, 76, 1972.

[0194] The compounds of formula (VI), (IX) and (XI) are known compoundsor they are prepared using methods analogous to those used to prepareknown compounds, such as those described in J. March, Advanced OrganicChemistry, 3rd Edition (1985), Wiley Interscience.

[0195] Suitable conversions of one compound of formula (I) into anothercompound of formula (I) includes converting a compound of formula (I)wherein X represents a hydroxy group or an alkoxy group into a compoundof formula (I) wherein X represents a different alkoxy group or a moietyof the above defined formula NR_(s)R_(t). Such conversions are shownbelow in Scheme (IV):

[0196] wherein, subject to any qualification mentioned below, R₂, R₃,R₄, R₅, R₆, R₇, R₈ and X are as defined in relation to the compounds offormula (I), R_(s′) is R_(s) or a protected form thereof, R_(t′) isR_(t) or a protected form thereof and R′ is X when X is an alkoxy group.

[0197] The conversion of one compound of formula (I) into anothercompound of formula (I) may be carried out using the appropriateconventional procedure; for example, the above mentioned conversion of acompound wherein X represents a hydroxy group or an alkoxy group into acompound wherein X represents a moiety of the above defined formulaNR_(s)R_(t) or another alkoxy group may be carried out as follows:

[0198] (i) when X is alkoxy, by basic hydrolysis, using for examplepotassium hydroxide, to provide a compound of formula (I) wherein X ishydroxy, and thereafter (a) for preparing compounds wherein X representsa moiety of the above defined formula NR_(s)R_(t), treating with acompound of formula HNR_(s′)R_(t′) wherein R_(s′) and R_(t′) are asdefined above or (b) for preparing compounds of formula (I) wherein Xrepresents alkoxy, by treating with a compound of formula R′OH whereinR′ is the required alkyl group; and thereafter optionally deprotecting;or

[0199] (ii) when X is hydroxy, by using analogous procedures to thosementioned above in (i).

[0200] Preferably the reaction with the compounds of formulaHNR_(s′)R_(t′) or with compounds of formula R′OH takes place afteractivation of the carboxylic group.

[0201] A carboxyl group may be activated in conventional manner, forexample, by conversion into an acid anhydride, acid halide, acid azideor an activated ester such as cyanomethyl ester, thiophenyl ester,p-nitrophenyl ester, p-nityrothiophenyl ester, 2,4,6-trichlorophenylester, pentachlorophenyl ester, pentafluorophenyl ester,N-hydroxyphthalimido ester, 8-hydroxypiperidine ester,N-hydroxysuccinimide ester, N-hydroxybenzotriazole ester, or thecarboxyl group may be activated using a carbodiimide such asN,N′-dicyclohexylcarbodiimide (DCC) or1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (WSC),either in the presence or the absence of hydroxybenzotriazole (HOBt) or1-hydroxy-7-azabenzotriazole (HOAt); or it may be activated usingN,N′-carbonyldiimidazole, Woodward-K reagent, Castro's reagent or anisoxazolium salt.

[0202] Condensation of an activated carboxyl group with an amino groupor with an alcoholic group may be carried out in the presence of a base,in any suitable solvent. Suitable bases include organic bases, such astriethylamine, trimethylamine, N,N-diisopropylethylamine (DIPEA),pyridine, N,N-dimethylaniline, 4-dimethylaminopyridine (DMAP),N-methylmorpholine, 1,5-diazabicyclo[4.3.0]-5-nonene (DBN),1,5-diazabicyclo[5.4.0]-5-undecene (DBU), 1,5-diazabicyclo[2.2.2]octane(DABCO), and inorganic bases, such as potassium carbonate. Suitablesolvents include conventionally used solvents, for example DMF, dimethylsulfoxide (DMSO), pyridine, chloroform, dioxane, dichloromethane, THF,ethyl acetate, acetonitrile, N-methylpyrrolidone andhexamethylphosphoric triamide and mixtures thereof. The reactiontemperature may be within the usual temperature range employed in thistype of condensation reaction, and generally in the range of about −40°C. to about 60° C., preferably from about −20° C. to about 40° C.

[0203] When the reaction is carried out in the presence of a suitablecondensing agent, for example a carbodiimide, N,N′-carbonyldiimidazole,Woodward-K reagent, Castro's reagent or the like, the condensing agentis preferably employed in an amount from equimolar to about 5 times themolar quantity of the starting material and the reaction is performed ina suitable solvent for example a halogenated hydrocarbon such asdichloromethane, chloroform, carbon tetrachloride, tetrachloroethane orthe like; an ether such as dioxane, THF, dimethoxyethane or the like, aketone such as acetone, methyl ethyl ketone or the like; acetonitrile,ethyl acetate, DMF, dimethylacetamide, DMSO or the like. Preferably thecondensation is carried out in an anhydrous solvent, and at a reactiontemperature in the range of from about −10° C. to 60° C., preferablyabout 0° C. to room temperature.

[0204] Alternatively, conversion of one compound of formula (I) in whichX is O-alkyl into another compound of formula (I) in which X isNR_(s)R_(t) may be effected by treating the said compound of formula (I)directly with a compound of formula HNR_(s′)R_(t′) in the presence of atrialkylaluminium reagent such as trimethylaluminium ortriethylaluminium, according to known procedures, such as thosedisclosed in Tetrahedron Lett., 48, 4171 (1977); and, if necessary,deprotecting or converting the compound of formula (I) in which X isNR_(s′)R_(t′) into a compound of formula (I) in which X is NR_(s)R_(t).

[0205] The trialkylaluminium reagent is generally employed in the abovementioned reactions in an amount of from equimolar to about 5 times themolar quantity of the starting material, preferably 2-3 times the molarquantity of the starting material and the reaction is performed in asuitable solvent for example a halogenated hydrocarbon such asdichloromethane, chloroform, carbon tetrachloride, tetrachloroethane orthe like; an ether such as dioxane, THF, dimethoxyethane or the like.Preferably the condensation is carried out in an anhydrous solvent, andat a reaction temperature of about, generally −20° C. to 120° C.,preferably about 0° C. to the reflux temperature of the solvent.

[0206] Amines of general formula HNR_(s)R_(t) may be prepared using themethods known in the art for the preparation of amines, for example astaught in Houben-Weil, Methoden der Organischen Chemie, Vol. XI/1 (1957)and Vol. E16d/2 (1992), Georg Thieme Verlag, Stuttgart.

[0207] In particular, amines of the general formula HNR_(s)R_(t) whereinone of R_(s) and R_(t) represents hydrogen and the other represents amoiety (a), (b), (c), (d) (e) as defined above or a particular examplethereof, are prepared according to the methods summarised in Scheme (V)below:

[0208] wherein R is an alkyl or aryl group, R_(u) and R_(v) are asdefined above, X₆ to X₁₄ are as defined for (H2), A is a bond or analkylene chain, R₁₀ is hydrogen (in (ii) and (vii)) or halogen (in(iii)) and R₁₁ is an alkyl group, R₁₂ is alkyl or aryl, L and L₁ areleaving groups, for example halogen or mesylate, Y is halogen, Y₁ is aleaving group, for example a halogen and and Y₁ and Y₂ are leavinggroups such as halogens, for example Y₁ is chloride and Y₂ is bromine,Z₁ is N or CY₃ wherein Y₃ is selected from hydrogen, alkyl, alkoxy,alkylcarbonyl, aryl, aryloxy or arylcarbonyl.

[0209] The reactions of condensation in (i) are performed underconventional reaction conditions as described in J. March, AdvancedOrganic Chemistry, 3rd Edition, 1985, Wiley Interscience

[0210] The reduction of the amide function in (i) is suitably carriedout using known methods, for example by using mixed hydride reducingagents, such as lithium aluminium hydride and methods described in OrgSynth Coll Vol 4 564.

[0211] Protection of the primary amino group in (i) can entail the useof classical carbamate protecting agents such as t-butoxycarbonyl (Boc),benzyloxycarbonyl (Cbz) or fluorenylmethoxycarbonyl (Fmoc), or of thephthalimido protecting group. The synthesis and the removal of suchprotective groups is described in, for example, in Protective Groups inOrganic Synthesis, T. W Greene Ed., Wiley, New York, 1981

[0212] The reduction of the nitrile in (i) is suitably carried out usingknown methods, for example following the procedure described in J. Med.Chem., 39, 1514, (1996).

[0213] The reduction of the nitropyridine in (ii) is suitably carriedout using the method described in J. Org. Chem. 58, 4742 (1993).

[0214] The alkylation of the hydroxy-nitropyridine in (ii) may beeffected by using the method described in J. Org. Chem 55, 2964 (1990).

[0215] The displacement reaction in (iii) and (vii) is suitably carriedout using the method described in Helvetica Chemica Acta 47 (2),45(1964)

[0216] The reduction of the nitrile in (v) is suitably carried bycatalytic hydrogenation over platinium oxide.

[0217] The reduction of nitro group in (vii) is suitably carried outusing the method described in J. Org. Chem. 58, 4742 (1993).

[0218] The reaction of acid halide NC-A-COY to provide thedialkylphosphonate in (iv) is effected by following the proceduredescribed in J Org Chem 36, 3843 (1971).

[0219] The reaction of the azide with triphenylphosphine in (v) iscarried out in wet tetrahydrofuran as described in Bull Soc Chim Fr1985, 815.

[0220] The azides in (v) are prepared as shown usingazidotrimethylsilane, following the procedure described in Synthesis1995, 376.

[0221] The reaction of compound Y₁-A-Y₂ and the amine derivative in (v)proceeds under conventional displacement reaction conditions.

[0222] The reactions in (vi) can be performed using known, conventionalmethods, as described in J. March, Advanced Organic Chemistry, 3rdEdition, 1985, Wiley Interscience. For example, oxidation can beperformed using oxidising agents such as chromic acid (Jones reagent);reductive amination of the ketone in can be performed with benzylamineto give an imine intermediate which is then reduced using known methodsand reducing agents such as sodium borohydride or lithium aluminiumhydride. Debenzylation can then be performed again using conventionalmethods, for example with hydrogen in the presence of a catalyst such aspalladium on charcoal. Protection of ketone as the ethylene ketal can beperformed with ethylene glycol under acidic catalysis; acylations oralkylations can be performed by treating the suitable piperidinederivatives with acyl or alkyl halides in the presence of an inorganicor organic base; deprotection of the dioxolane to the ketone can beeffected by acidic treatment in aqueous or alcoholic solvents.Protection on the primary amino group in 4 aminopiperidines can entailthe use of classical carbamate protecting agents such ast-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) orfluorenylmethoxycarbonyl (Fmoc), or of the phthalimido protecting group:the synthesis and the removal of such protective groups is described in,for example, in Protective Groups in Organic Synthesis, T. W Greene Ed.,Wiley, New York, 1981. 4-Oxopiperidines can be converted into thecorresponding oximes by treatment with hydroxyl- or alkoxyl-amine in asuitable solvent; reduction of the oxime to amine can be performed usingconventional reducing agents such as lithium aluminium hydride or sodiumcyanoborohydryde.

[0223] The starting materials in the above reactions (i), (ii), (iii),(iv), (v), (vi) and (vii) are known, commercially available compounds.

[0224] A compound of formula (I) or a solvate thereof may be isolatedfrom the above mentioned processes according to standard chemicalprocedures.

[0225] The preparation of salts and/or solvates of the compounds offormula (I) may be performed using the appropriate conventionalprocedure.

[0226] If required mixtures of isomers of the compounds of the inventionmay be separated into individual stereoisomers and diastereoisomers byconventional means, for example by the use of an optically active acidas a resolving agent. Suitable optically active acids which may be usedas resolving agents are described in “Topics in Stereochemistry”, Vol.6, Wiley Interscience, 1971, Allinger, N. L. and Eliel, W. L. Eds.

[0227] Alternatively, any enantiomer of a compound of the invention maybe obtained by stereospecific synthesis using optically pure startingmaterials of known configuration.

[0228] The absolute configuration of compounds may be determined byconventional methods such as X-ray crystallographic techniques.

[0229] The protection of any reactive group or atom, may be carried outat any appropriate stage in the aforementioned processes. Suitableprotecting groups include those used conventionally in the art for theparticular group or atom being protected. Protecting groups may beprepared and removed using the appropriate conventional procedure, forexample OH groups, including diols, may be protected as the silylatedderivatives by treatment with an appropriate silylating agent such asdi-tert-butylsilylbis(trifluoromethanesulfonate): the silyl group maythen be removed using conventional procedures such as treatment withhydrogen fluoride, preferably in the form of a pyridine complex andoptionally in the presence of alumina, or by treatment with acetylchloride in methanol. Alternatively benzyloxy groups may be used toprotect phenolic groups, the benzyloxy group may be removed usingcatalytic hydrogenolysis using such catalysts as palladium (II) chlorideor 10% palladium on carbon.

[0230] Amino groups may be protected using any conventional protectinggroup, for example tert-butyl esters of carbamic acid may be formed bytreating the amino group with di-tert-butyldicarbonate, the amino groupbeing regenerated by hydrolysing the ester under acidic conditions,using for example hydrogen chloride in ethyl acetate or trifluoroaceticacid in methylene dichloride. An amino group may be protected as abenzyl derivative, prepared from the appropriate amine and a benzylhalide under basic conditions, the benzyl group being removed bycatalytic hydrogenolysis, using for example a palladium on carboncatalyst.

[0231] Indole NH groups and the like may be protected using anyconventional group, for example benzenesulphonyl, methylsulphonyl,tosyl, formyl, acetyl (all of them removable by treatment with alkalinereagents), benzyl (removable either with sodium in liquid ammonia orwith AlCl₃ in toluene), allyl (removable by treatment with rhodium (III)chloride under acidic conditions), benzyloxycarbonyl (removable eitherby catalytic hydrogenation or by alkaline treatment), trifluoroacetyl(removable by either alkaline or acidic treatment), t-butyldimethylsilyl(removable by treatment with tetrabutylammonium fluoride),2-(trimethylsilyl)ethoxymethyl (SEM) (removable by treatment withtetrabutylammonium fluoride in the presence of ethylendiamine),methoxymethyl (MOM) or methoxyethyl (MEM) groups (removed by mild acidictreatment).

[0232] Carboxyl groups may be protected as alkyl esters, for examplemethyl esters, which esters may be prepared and removed usingconventional procedures, one convenient method for convertingcarbomethoxy to carboxyl is to use aqueous lithium hydroxide.

[0233] A leaving group or atom is any group or atom that will, under thereaction conditions, cleave from the starting material, thus promotingreaction at a specified site. Suitable examples of such groups unlessotherwise specified are halogen atoms, mesyloxy,p-nitrobenzensulphonyloxy and tosyloxy groups.

[0234] The salts, esters, amides and solvates of the compounds mentionedherein may as required be produced by methods conventional in the art:for example, acid addition salts may be prepared by treating a compoundof formula (I) with the appropriate acid.

[0235] Esters of carboxylic acids may be prepared by conventionalesterification procedures, for example alkyl esters may be prepared bytreating the required carboxylic acid with the appropriate alkanol,generally under acidic conditions.

[0236] Amides may be prepared using conventional amidation procedures,for example amides of formula CONR_(s)R_(t) may be prepared by treatingthe relevant carboxylic acid with an amine of formula HN R_(s)R_(t)wherein R_(s) and R_(t) are as defined above. Alternatively, a C₁₋₆alkyl ester such as a methyl ester of the acid may be treated with anamine of the above defined formula HNR_(s)R_(t) to provide the requiredamide.

[0237] As mentioned above the compounds of the invention are indicatedas having useful therapeutic properties:

[0238] The present invention therefore provides a method for thetreatment and/or prophylaxis of diseases associated with over activityof osteoclasts in mammals which method comprises the administration ofan effective non-toxic amount of a selective inhibitor of mammalianosteoclasts.

[0239] A suitable selective inhibitor of a mammalian osteoclast is aselective inhibitor of the vacuolar ATPase located on the ruffled borderof mammalian osteoclasts.

[0240] One particular selective inhibitor of mammalian vacuolar ATPaseis a compound of formula (I), or a pharmaceutically acceptable saltthereof, or a pharmaceutically acceptable solvate thereof.

[0241] Thus, the present invention further provides a method for thetreatment of osteoporosis and related osteopenic diseases in a human ornon-human mammal, which comprises administering an effective, non-toxic,amount of a compound of formula (I) or a pharmaceutically acceptablesolvate thereof, to a human or non-human mammal in need thereof.

[0242] In a further aspect, the present invention provides an inhibitorof a mammalian, especially human, osteoclasts, for example a compound offormula (I) or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate thereof, for use as an activetherapeutic substance.

[0243] The preferred mammal is human. Mammalian osteoclasts arepreferably human osteoclasts.

[0244] In particular the present invention provides a compound offormula (I) or a pharmaceutically acceptable salt thereof and/or apharmaceutically acceptable solvate thereof, for use in the treatment ofand/or prophylaxis of osteoporosis and related osteopenic diseases.

[0245] Of particular interest is the osteoporosis associated with theperi and post menopausal conditions. Also encompassed are the treatmentand prophylaxis of Paget's disease, hypercalcemia associated with boneneoplasms and all the types of osteoporotic diseases as classified belowaccording to their etiology:

[0246] Primary osteoporosis

[0247] Involutional

[0248] Type I or postmenopausal

[0249] Type II or senile

[0250] Juvenile

[0251] Idiopathic in young adults

[0252] Secondary osteoporosis

[0253] Endocrine abnormality

[0254] Hyperthyroidism

[0255] Hypogonadism

[0256] Ovarian agenesis or Turner's syndrome

[0257] Hyperadrenocorticism or Cushing's syndrome

[0258] Hyperparathyroidism

[0259] Bone marrow abnormalities

[0260] Multiple myeloma and related disorders

[0261] Systemic mastocytosis

[0262] Disseminated carcinoma

[0263] Gaucher's disease

[0264] Connective tissue abnormalities

[0265] Osteogenesis imperfecta

[0266] Homocystinuria

[0267] Ehlers-Danlos syndrome

[0268] Marfan's syndrome

[0269] Menke's syndrome

[0270] Miscellaneous causes

[0271] Immobilisation or weightlessness

[0272] Sudeck's atrophy

[0273] Chronic obstructive pulmonary disease

[0274] Chronic alcoholism

[0275] Chronic heparin administration

[0276] Chronic ingestion of anticonvulsant drugs

[0277] In addition the invention encompasses the treatment of tumours,especially those related to renal cancer, melanoma, colon cancer, lungcancer and leukemia, viral conditions (for example those involvingSemliki Forest virus, Vesicular Stomatitis virus, Newcastle Diseasevirus, Influenza A and B viruses, HIV virus), ulcers (for examplechronic gastritis and peptic ulcer induced by Helicobacter pylori), foruse as immunosupressant agents in autoimmune diseases andtransplantation, antilipidemic agents for the treatment and/orprevention of hypercholesterolemic and atherosclerotic diseases and tobe useful for the treatment of AIDS and Alzheimer's disease. Thesecompounds are also considered useful in treating angiogenic diseases,i.e. those pathological conditions which are dependent on angiogenesis,such as rheumatoid arthritis, diabetic retinopathy, psoriasis and solidtumours

[0278] A selective inhibitor of the pharmacological activity of humanosteoclast cells such as a compound of formula (I), or apharmaceutically acceptable salt thereof and/or a pharmaceuticallyacceptable solvate thereof, may be administered per se or, preferably,as a pharmaceutical composition also comprising a pharmaceuticallyacceptable carrier.

[0279] Accordingly, the present invention also provides a pharmaceuticalcomposition comprising a selective inhibitor of the pharmacologicalactivity of human osteoclast cells, in particular the bone resorptionactivity of human osteoclast cells associated with abnormal loss of bonemass, and a pharmaceutically acceptable carrier thereof.

[0280] A particular inhibitor of human osteoclast cells is a selectiveinhibitor of human osteoclast vacuolar ATPase such as a compound offormula (I), or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate thereof, and a pharmaceuticallyacceptable carrier thereof.

[0281] Active compounds or a pharmaceutically acceptable salt thereofand/or a pharmaceutically acceptable solvate thereof is normallyadministered in unit dosage form.

[0282] An amount effective to treat the disorders hereinbefore describeddepends upon such factors as the efficacy of the active compounds, theparticular nature of the pharmaceutically acceptable salt orpharmaceutically acceptable solvate chosen, the nature and severity ofthe disorders being treated and the weight of the mammal. However, aunit dose will normally contain 0.01 to 50 mg, for example 1 to 25 mg,of the compound of the invention. Unit doses will normally beadministered once or more than once a day, for example 1, 2, 3, 4, 5 or6 times a day, more usually 1 to 3 or 2 to 4 times a day such that thetotal daily dose is normally in the range, for a 70 kg adult of 0.01 to250 mg, more usually 1 to 100 mg, for example 5 to 70 mg, that is in therange of approximately 0.0001 to 3.5 mg/kg/day, more usually 0.01 to 1.5mg/kg/day, for example 0.05 to 0.7 mg/kg/day.

[0283] At the above described dosage range, no toxicological effects areindicated for the compounds of the invention.

[0284] The present invention also provides a method for the treatment oftumours, especially those related to renal cancer, melanoma, coloncancer, lung cancer and leukemia, viral conditions (for example thoseinvolving Semliki Forest, Vesicular Stomatitis, Newcastle Disease,Influenza A and B, HIV viruses), ulcers (for example chronic gastritisand peptic ulcer induced by Helicobacter pylori), autoimmune diseasesand transplantation, for the treatment and/or prevention ofhypercholesterolemic and atherosclerotic diseases, AIDS and Alzheimer'sdisease, angiogenic diseases, such as rheumatoid arthritis, diabeticretinopathy, psoriasis and solid tumours, in a human or non-humanmammal, which comprises administering an effective, non-toxic, amount ofa compound of formula (I) or a pharmaceutically acceptable solvatethereof, to a human or non-human mammal in need thereof.

[0285] In such treatments the active compound may be administered by anysuitable route, e.g. by the oral, parenteral or topical routes. For suchuse, the compound will normally be employed in the form of apharmaceutical composition in association with a human or veterinarypharmaceutical carrier, diluent and/or excipient, although the exactform of the composition will naturally depend on the mode ofadministration.

[0286] Compositions are prepared by admixture and are suitably adaptedfor oral, parenteral or topical administration, and as such may be inthe form of tablets, capsules, oral liquid preparations, powders,granules, lozenges, pastilles,-reconstitutable powders, injectable andinfusable solutions or suspensions, suppositories and transdermaldevices. Orally administrable compositions are preferred, in particularshaped oral compositions, since they are more convenient for generaluse.

[0287] Tablets and capsules for oral administration are usuallypresented in a unit dose, and contain conventional excipients such asbinding agents, fillers, diluents, tabletting agents, lubricants,disintegrants, colourants, flavourings, and wetting agents. The tabletsmay be coated according to well known methods in the art.

[0288] Suitable fillers for use include cellulose, mannitol, lactose andother similar agents. Suitable disintegrants include starch,polyvinylpyrrolidone and starch derivatives such as sodium starchglycollate. Suitable lubricants include, for example, magnesiumstearate. Suitable pharmaceutically acceptable wetting agents includesodium lauryl sulphate.

[0289] These solid oral compositions may be prepared by conventionalmethods of blending, filling, tabletting or the like. Repeated blendingoperations may be used to distribute the active agent throughout thosecompositions employing large quantities of fillers. Such operations are,of course, conventional in the art.

[0290] Oral liquid preparations may be in the form of, for example,aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs,or may be presented as a dry product for reconstitution with water orother suitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

[0291] For parenteral administration, fluid unit dose forms are preparedcontaining a compound of the present invention and a sterile vehicle.The compound, depending on the vehicle and the concentration, can beeither suspended or dissolved. Parenteral solutions are normallyprepared by dissolving the compound in a vehicle and filter sterilisingbefore filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anaesthetic, preservatives andbuffering agents are also dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum.

[0292] Parenteral suspensions are prepared in substantially the samemanner except that the compound is suspended in the vehicle instead ofbeing dissolved and sterilised by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniformdistribution of the active compound.

[0293] For topical administration, the composition may be in the form ofa transdermal ointment or patch for systemic delivery of the activecompound and may be prepared in a conventional manner, for example, asdescribed in the standard textbooks such as ‘DermatologicalFormulations’—B. W. Barry (Drugs and the Pharmaceutical Sciences—Dekker)or Harrys Cosmeticology (Leonard Hill Books).

[0294] The present invention also provides the use of a selectiveinhibitor of the biological activity of human osteoclast cells, inparticular the bone resorption activity of human osteoclast cellsassociated with abnormal loss of bone mass, compound of formula (I), ora pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate thereof, for the manufacture of a medicament for thetreatment and/or prophylaxis of diseases associated with over activityof osteoclasts in mammals, such as the treatment and/or prophylaxis ofosteoporosis and related osteopenic diseases.

[0295] The present invention also provides the use of a selectiveinhibitor of the biological activity of human osteoclast cells, inparticular the bone resorption activity of human osteoclast cellsassociated with abnormal loss of bone mass, for the manufacture of amedicament for the treatment of tumours, especially those related torenal cancer, melanoma, colon cancer, lung cancer and leukemia, viralconditions (for example those involving Semliki Forest, VesicularStomatitis, Newcastle Disease, Influenza A and B, HIV viruses), ulcers(for example chronic gastritis and peptic ulcer induced by Helicobacterpylori), autoimmune diseases and transplantation, for the treatmentand/or prevention of hypercholesterolemic and atherosclerotic diseases,AIDS and Alzheimer's disease, angiogenic diseases, such as rheumatoidarthritis, diabetic retinopathy, psoriasis and solid tumours.

[0296] In one preferred aspect the inventions herein comprisingcompositions, treatment methods and pharmaceutical uses of a selectiveinhibitor of the biological activity of mammalian, including human,osteoclast cells exclude the compositions, treatment methods andpharmaceutical uses of the compounds of formula (I) of WO96/21644 and inanother aspect the specific examples of WO96/21644.

[0297] No unacceptable toxicological effects are expected with compoundsof the invention when administered in accordance with the invention. Asis common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned.

[0298] The following, descriptions, examples and pharmacological methodsillustrate the invention but do not limit it in any way.

[0299] Preparation 1

[0300] Ethyl alpha-oxo-3-(2-nitro-4,5dichlorophenyl)propanoate. To asuspension of potassium (49.2 g, 1.26 mol) in anhydrous diethyl ether(500 ml), a solution of absolute EtOH (319 ml) and anhydrous diethylether (260 ml) was added dropwise under nitrogen during a period of fourhours. The resulting solution was diluted with anhydrous diethyl ether(1200 mL) and then diethyl oxalate (171 ml, 1.26 mol) was added dropwisein about 30 minutes. To the resulting yellow mixture, a solution of2-nitro-4,5-dichlorotoluene (260 g, 1.26 mmol), prepared as described byCohen and Dakin in J. Chem. Soc., 79, 1133, in anhydrous diethyl ether(450 ml) was added dropwise in one hour at RT. Stirring was continuedfor additional three hours and the dark-brown mixture was settled at RTfor two days. The potassium salt was collected by suction and dried togive a dark-brown powder. This was suspended in a mixture of water (400ml) and ethyl acetate (400 ml), then acidified with 10% HCl. The organicphase was washed with brine, aqueous sat. NaHCO₃ and again brine, thenit was dried with MgSO₄. Evaporation produced 239 g of title compound(781 mmol, yield 62.0%) as a light brown solid that was used as such forthe next step, m.p.=92-94° C.

[0301] Preparation 2

[0302] Ethyl 5,6-dichloroindole-2-carboxylate. A mixture of ethylalpha-oxo-3-(2-nitro-4,5-dichlorophenyl)propanoate (200 g, 653 mmol) andiron powder (320 g, 5.75 mol) in EtOH/AcOH {fraction (1/1)} (2.5 l) wasrefluxed for two hours. After cooling, the resulting mixture wasevaporated under vacuum and the solid residue was dissolved in THF (4l). The solid residue was filtered on Fluosil and then washed withadditional THF (2 l). The pooled organic phases were concentrated togive a dark residue (203 g). This was treated with AcOEt/CH₂Cl₂ and theremaining solid was filtered off. Evaporation produced 120 g of titlecompound (465 mmol, yield 71.2%) that was used as such for the nextstep, m.p.=215-218° C.

[0303] Preparation 3

[0304] 5,6-Dichloroindole-2-methanol. To an ice cold stirred 1M solutionof LiAlH₄ in anhydrous THF (800 ml, 800 mmol) under argon, ethyl5,6-dichloroindole-2-carboxylate (118 g, 457 mmol), dissolved inanhydrous THF (1 l), was added dropwise while keeping the temperaturebelow 5°. Stirring at 0° was continued for one hour, then the reactionwas quenched with water (35 ml), 15% aq. NaOH (35 ml) and water (70 ml).The mixture was filtered on a Celite pad and washed with THF (2×500 ml).The organic phase was dried (MgSO₄) and concentrated to give a residue(80 g) that was chromatographed with AcOEt/n-heptane ½ to give 52.0 g ofpure title compound (241 mmol, yield 52.7%) as an oil.

[0305] Preparation 4

[0306] 5,6-Dichloroindole-2-carboxaldehyde. A solution of5,6-dichloroindole-2-methanol (43 g, 199 mmol) in diethyl ether (1.3 l)was treated with activated MnO₂ (64 g, 730 mmol) and stirred for 15hours at room temperature. Additional MnO₂ (20 g, 230 mmol) was addedand stirring continued for 5 h. The suspension was filtered on a Celitepad, then the pad was washed with diethyl ether and warm acetone. Thepooled organic phases were concentrated to give 38.5 g of the titlecompound (180 mmol, yield 90.4%) that was used as such in the next step,m.p.=207-208° C.

[0307] Preparation 5

[0308] Method A). Ethyl (E)-3-(5,6-dichloroindol-2-yl)-2-propenoate.5,6-Dichloro indole-2-carboxaldehyde (35 g, 164 mmol) was dissolved intoluene (1.5 l) under argon, then(ethoxycarbonylmethylene)triphenylphosphorane (60 g, 176 mmol) was addedand the solution was refluxed for 3 h. The solvent was evaporated underreduced pressure and the residue chromatographed on silicagel withAcOEt/n-heptane ¼ to give 28.0 g of pure title compound, m.p.=188-190°C. (yield 60.1%).

[0309] Method B). Ethyl (E)-3-(5,6-dichloroindol-2-yl)-2-propenoate. Toa solution of triethyphosphonoacetate (32.9 g, 147 mmol) in THF (150ml), NaH (5.95, 148 mmol) was added portionwise under nitrogenmaintaining the temperature between 0-5° C. in 30 min. After reachingroom temperature, 5,6-dichloro-1H-indol-2-carboxaldehyde (29 g, 135.5mmol), dissolved in THF (200 ml), was added dropwise maintaining theinternal temperature around 20° C. (about 1 h). The solvent wasevaporated under reduced pressure and the residue was treated with H₂O(200 ml) and EtOAc (500 ml). The organic layer was washed with brine,dried over Na₂SO₄ and evaporated to dryness obtaining a residue that wastriturated with hexane, filtered and dried under vacuum affording 34.5 gof the title compound, m.p.=188-190° C. (yield=89.6%).

[0310] Preparation 6

[0311] (E)-3-(5,6-Dichloroindol-2-yl)-2-propen-1-ol. To a solution ofethyl (E)-3-(5,6-dichloroindol-2-yl)-2-propenoate (28 g, 98.5 mmol) indry THF (500 ml) stirred under argon at −20° DIBAL (1M solution inhexane, 200 mmol) was added dropwise while keeping the temperature below−20°. The stirring was continued for one hour, then the reaction wasquenched with water (70 m). After warming to RT diethyl ether (350 m)was added and the suspension was filtered on a Celite pad. The pad waswashed with diethyl ether (3×100 ml), then the pooled organic phase wasdried (MgSO₄) and evaporated to give 23.85 g of the title compound (98.5mmol, yield 100%) that was used as such in the next step.

[0312] Preparation 7

[0313] (E)-3-(5,6-Dichloroindol-2-yl)-2-propenaldehyde. To a solution of(E) 3-(5,6-dichloroindol-2-yl)-2-propen-1-ol (23.8 g, 98.3 mmol) indiethyl ether (800 ml) activated MnO₂ (71 g, 8.76 mol) and NaCl (60 g)were added and the resulting suspension stirred for one day at RT. Itwas then filtered on a Celite pad repeatedly washed with AcOEt and theorganic phase dried (MgSO₄) and evaporated to give 21.0 g of the titlecompound (87.5 mmol, yield 89.0%) that was used as such in the nextstep.

[0314] Preparation 8

[0315] Methyl(2Z,4E)-5-(5,6-dichloroindol-2-yl)-2-methoxy-2,4-pentadienoate. Asolution of (E) 3-(5,6-dichloroindol-2-yl)-2-propenaldehyde (15 g, 62.5mmol), methyl 2-methoxy-2-(triphenylphosphonium)acetate bromide (31 g,69.6 mmol) and DBU (10.5 mL, 70.1 mmol) was refluxed for 4 h. Thesolvent was evaporated and the crude chromatographed on silicagel withAcOEt/n-heptane ¼ to give 14.5 g of pure title compound (44.5 mmol,yield 71.1%) after trituration with diisopropyl ether, m.p.=203-204° C.

[0316] Preparation 9

[0317] (2Z,4E)-5-(5,6-Dichloroindol-2-yl)-2-methoxy-2,4-pentadienoicacid. A suspension of methyl(2Z,4E)-5-(5,6-dichloroindol-2-yl)-2-methoxy-2,4-pentadienoate (10 g,30.7 mmol) and KOH (3.6 g, 64.2 mmol) in EtOH/water {fraction (1/1)}(460 ml) was refluxed for 3 h. The suspension after cooling to RT waspoured into water (1.5 l), it was acidified with 2N HCl and extractedwith AcOEt (2×1 l). The organic phase was washed with water and dried(MgSO₄), then concentrated and the residue taken up with CH₂Cl₂.Filtration and drying in the oven at 50° produced 9.5 g of pure titlecompound (30.4 mmol, yield 99.1%), m.p.=249-250° C.

[0318]¹H-NMR (DMSO-d₆): 11.81 (bs, 1H); 7.77 (s, 1H); 7.53 (s, 1H); 7.20(dd, 1H); 6.95 (d, 1H); 6.84 (d, 1H); 6.61 (s, 1H); 3.74 (s, 3H)

[0319] Preparation 10

[0320] 1,2,2,6,6-Pentamethyl-4-piperidone hydroiodide. A solution of2,2,6,6-tetramethyl-4-piperidone monohydrate (40 g, 23.1 mmol) andmethyl iodide (98.31 g, 69.3 mmol) in isopropyl alcohol (25 mL) wasstirred at RT for 48 hours. The resulting suspension was filtered, thesolid residue was dried and recrystallized from MeOH. After filtrationand repeated washings with MeOH the solid was dried giving pure titlecompound (31.6 g, 10.6 mmol, yield 46.0%) as pale brown crystals.

[0321] Preparation 11

[0322] 1,2,2,6,6-Pentamethyl-4-piperidone oxime. A suspension of1,2,2,6,6-pentamethyl-4-piperidone hydroiodide (3 g, 10.1 mmol) andhydroxylamine hydrochloride (980 mg, 14 mmol) in water (6 ml) wasstirred at RT for 15 minutes. Solid NaOH was added until basic pH andthickening of the suspension. Water (3 ml) was added and stirring at RTwas continued overnight. The suspension was filtered and the solidwashed with water (few ml) and dried. The solid was then dissolved inEt₂O, the solution was dried (MgSO₄) and concentrated to give afterdrying pure title compound (1.55 g, 8.41 mmol, yield 83.3%) as whitecrystals.

[0323] Preparation 12

[0324] 4-Amino-1,2,2,6,6-pentamethyl-4-piperidine. LiAlH₄ (925 mg, 24.4mmol) was added under stirring at 0° under Ar to anhydrous THF (100 ml),followed by 1,2,2,6,6-pentamethyl-4-piperidone oxime (1.50 g, 8.14mmol). The suspension was refluxed for 2 hours, then cooled to RT andstirred overnight. After cooling to 0° water (0.9 ml), 15% aq. NaOH (0.9ml) and water (2.8 ml) were carefully added dropwise. The suspension wasstirred for 15 min at RT, then MgSO₄ was added and stirring continuedfor 30 minutes. After filtration, the liquid was concentrated and theoily residue chromatographed on silicagel (CH₂Cl₂/MeOH/aq.NH₃ 95/5/1).The collected fractions were pooled and concentrated to give pure titlecompound (750 mg, 4.40 mmol, yield 54.1%) as a yellow oil.

[0325] Preparation 13

[0326] (2Z,4E)-5-(Indol-2-yl)-2-methoxy-2,4-pentadienoic acid wasprepared from 2-indolecarbaldehyde (Heterocycles, 1984, 22, 1211) usingthe reaction sequence described in Preparations 5-9. m.p.=189-190° C.

[0327] Preparation 14

[0328] Ethyl 5-trifluoromethyl-2-indolecarboxylate.5-Trifluoromethylphenylhydrazine (5 g, 28.4 mmol) was treated with ethylpyruvate (3.3 ml, 30 mmol) in ethanol (15 ml) giving, after filtration,5.4 g of the corresponding phenylhydrazone as a white powder,m.p.=134-137° C. This compound (5.4 g, 19.7 mmol) was refluxed for 3 hin toluene (150 ml) in the presence of anhydrous p-toluensulfonic acid(6 g, 34.8 mmol) obtaining 0.9 g (18%) of the title compound as a yellowpowder, m.p.=153-154° C.

[0329] Preparation 15

[0330](2Z,4E)-5-(5-Trifluoromethylindol-2-yl)-2-methoxy-2,4-pentadienoic acidwas prepared from ethyl 5-trifluoromethyl-2-indolecarboxylate using thereaction sequence described in Preparations 3-9. m.p.=191-193° C.

[0331] Preparation 16

[0332] Ethyl 5-bromo-2-indolecarboxylate was prepared from5-bromophenylhydrazine and ethyl piruvate using the procedure describedin Preparation 14, m.p.=160-164° C.

[0333] Preparation 17

[0334] (2Z,4E)-5-(5-Bromoindol-2-yl)-2-methoxy-2,4-pentadienoic acid wasprepared from ethyl 5-bromo-2-indolecarboxylate using the reactionsequence described in Preparations 3-9, m.p.=208-210° C.

[0335] Preparation 18

[0336] 2,6-Dimethyl-4-(2-pyrimidinyl)piperazine dihydrochloride Asolution of 1.71 g (15 mmol) of 2,6-dimethylpiperazine and 1.14 g (10mmol) of 2-chloropyrimidine in 25 ml ethanol was refluxed for 16 hours.The reaction mixture was concentrated under reduced pressure, dissolvedin 25 ml of water and extracted twice with 50 ml of methylene chloride.The organic phase was dried over MgSO₄ and concentrated under reducedpressure. The residue was dissolved in acetonitrile and treated with asolution of anhydrous HCl in ethanol. The salt was filtered and dried invacuo to afford 1.70 g of the title compound.

[0337] Preparation 19

[0338] 3-[2,6-Dimethyl-4-(2-pyrimidinyl)piperazin-1-yl]propylamide. Amixture of 1.1 g (4.1 mmol) of 2,6-dimethyl-4-(2-pyrimidinyl)piperazinedihydrochloride, 0.45 g (4.1 mmol) of 3-chloropropionamide, 3 g of 30%KF on Clarcel® in 25 ml acetonitrile was heated for 72 hours at 150° C.in a close vessel. After cooling to room temperature the mixture wasfiltered over a filtration aid and concentrated under reduced pressure.

[0339] The residue was dissolved in water, alkalinised with aqueous 1NNaOH and extracted twice with 25 ml methylene chloride. The organicphase was dried over MgSO₄ and concentrated under reduced pressure. Theresidue was then purified by chromatography on silicagel (AcOEt, EtOH,NH₄OH: 45, 5, 1) to afford 0.2 g of the title compound, mp.=125° C.

[0340] Preparation 20

[0341] 3-[2,6-Dimethyl-4-(2-pyrimidinyl)piperazin-1-yl]propylamine. 50mg (1.54 mmol) of LiAlH₄ were added to a solution of 0.2 g (0.77 mmol)of 3-[2,6-dimethyl-4-(2-pyrimidinyl)piperazin-1-yl]propylamide in 5 mlof diethylether and 5 ml of THF. The mixture was stirred one hour atroom temperature and one additional hour at reflux, then the reactionwas quenched by successive addition of 50 ul of water, 50 ul of 15%aqueous NaOH and 3×50 ul water. The mixture was diluted with diethylether, filtered, dried over MgSO₄ and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel(CH₂Cl₂, EtOH, NH₄OH: 45, 5, 1) to afford 0.037 g of the title compound.

[0342] Preparation 21

[0343] 3-[4-(2,6-Dimethylphenyl)piperazin-1-yl]propylamine.4-(2,6-Dimethylphenyl) piperazine (1 g, 5.23 mmol) in MeOH (10 ml) wascooled to 0° and 0.305 g (5.73 mmol) of acrilonitrile was added. Thereaction was stirred overnight at room temperature and evaporated undervacuum affording 1 g of crude3-[4-(2,6-dimethylphenyl)piperazin-1-yl]propionitrile as a waxy solid.This compound was dissolved in MeOH (60 ml), 2 ml 37% HCl andhydrogenated under pressure (40 psi) with 0.2 g of 10% Pd\C. Thereaction was filtered and evaporated to dryness obtaining 1 g of thetitle compound, as a hydrochloride salt, that was used without furtherpurification for the following reaction.

EXAMPLE 1

[0344](2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pentadienamide. A solution of(2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoic acid(736 mg, 3.65 mmol), 4-amino-1,2,2,6,6-pentamethylpiperidine (620 mg,3.65 mmol), 1-hydroxy-7-azabenzotriazole hydrate (474.5 mg, 3.65 mmol)and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (693.5mg, 3.65 mmol) in DMF (2 ml) was stirred at RT overnight. The solutionwas poured into brine (20 ml) and repeatedly extracted with EtOAc. Theorganic phase was washed with 5% aq. CaCO₃, dried (MgSO₄) and evaporatedunder vacuum. The residue was chromatographed on silica gel using ethylacetate:methanol:aq. ammonia (32%) 90:10:2 as eluent mixture. Thecollected fractions produced the pure title compound (0.8, yield 73%) asyellow crystals, m.p.=212° C.

[0345]¹H-NMR (200 MHz, DMSO-d₆): 1.02 (s, 6H); 1.08 (s, 6H); 1.44(t,2H); 1.62 (m, 2H); 2.18 (s, 3H); 3.70 (s, 3H); 4.07 (m, 1H); 6.6 (m,2H); 6.84 (d, 1H); 7.14 (dd, 1H); 7.51 (s, 1H); 7.75 (s, 1H); 7.91 (d,1H); 11.74 (s, 1H, exch with D2O)

[0346] Two other isomers were isolated from the column chromatography:

[0347](2E,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pentadienamide

[0348]¹H-NMR (200 MHz, THF-d₈,): 10.76 (s br, 1H); 8.19 (dd, 1H); 7.54(s, 1H); 7.40 (s, 1H); 6.93 (d br, 1H); 6.51 (d, 1H); 6.32 (d, 1H); 5.92(d, 1H); 4.25-4.12 (m, 1H); 3.70 (s, 3H); 2.25 (s, 3H); 1.72 (m, 2H);1.32 (dd, 2H); 1.10 (s, 12H).

[0349](2Z,4Z)-5-(5,6-Dichloro-1H-indol-2yl)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pentadienamide

[0350]¹H-NMR (200 MHz, THF-d₈,): 10.48 (s br, 1H); 7.58 (s, 1H); 7.44(s, 1H); 7.22 (d, 1H); 6.99 (d br, 1H); 6.61 (s br, 1H); 6.59 (dd, 1H);6.42 (d, 1H); 4.25-4.12 (m, 1H); 3.75 (s, 3H); 2.28 (s, 3H); 1.72 (m,2H); 1.33 (dd, 2H); 1.11 (s, 12H).

[0351] The following compounds were prepared according to the procedureof Example 1

Ex. No Name Rs Rt R1 R2 R3 R4 Ra R6 R7 R8 MP. (° C.) N.M.R. 2(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-(6-ethoxy-pyridin-3-yl)-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 273 ¹H NMR(DMSO-d₆): 1.30(t, 3H); 3.82(s, 3H);4.27(q, 2H); 6.62(s, 1H); 6.77-6.98(m, 3H); 7.25(dd, 1H); 7.53(s, 1H);7.77(s, 1H); 6.04(dd, 1H); 8.49(d, 1H); 10.04(s, 1H, exch with D₂O);11.81(s, 1H, exch with D₂O). 3 (2Z,4E)-N-(5-Chloropyridin-2-yl)-5-(5,6-dichloro-1H- indol-3-yl)-2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 284 dec. ¹H NMR(DMSO-d₆): 3.84(s, 3H); 6.64(s,1H); 6.90(d, 1H); 7.00(d, 1H); 7.25(dd, 1H); 7.54(s, 1H); 7.77(s, 1H);7.97(dd, 1H); 8.16(d, 1H); 8.43(d, 1H); 10.13(s, 1H, exch with D₂O);11.82(s, 1H, exch with D₂O) 4 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N- [(2,4-dimethoxy)pyridin-3-yl]-2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 1.75 ¹H NMR(DMSO-d₆): 3.42(s, 3H); 3.81(s, 6H);6.33(d, 1H); 6.59(s, 1H); 6.67(d, 1H); 6.87(d, 1H); 7.22(dd, 1H);7.53(s, 1H); 7.73(m, 2H), 8.77(s, 1H, exch with D₂O); 11.83(s, 1H, exchwith D₂O) 5 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-(2-methoxy-pyrimidin-5-yl)-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 290-291 ¹H NMR(DMSO-d₆): 3.84(s, 3H); 3.90(s,3H); 6.64(s, 1H); 6.88(d, 1H); 6.96(d, 1H); 7.25(dd, 1H); 7.54(s, 1H);7.77(s, 1H); 8.91(s, 2H); 10.25(s, 1H, exch with D₂O); 11.82(s, 1H, exchwith D₂O) 6 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-(5-methoxy-pyridin-3-yl)-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 235-236 ¹H NMR(DMSO-d₆): 3.84(s, 3H); 3.85(s,3H); 6.64(s, 1H); 6.87(d, 1H); 6.97(d, 1H); 7.27(dd, 1H); 7.54(s, 1H);7.77(s, 1H); 7.96(m, 1H); 8.11(d, 1H); 8.67(d, 1H); 10.27(s, 1H, exchwith D₂O); 11.84(s, 1H, exch with D₂O) 7 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N-(3- (4-benzoylpiperazin-1- yl)propyl]-2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 232 ¹H NMR(DMSO-d₆): 1.64(m, # 2H); 2.35(m, 6H);3.19-3.26(m 4H); 3.44-3.62(m, 2H); 3.72(s, 3H); 6.58(s, 1H); 6.65(d,1H); 6.85(d, 1H); 7.17(dd, 1H); 7.36-7.46(m, 5H); 7.51(s, 1H); 7.75(s,1H); 8.25(t, 1H, exch with D₂O); 11.75(s, 1H, exch with D₂O) 8(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[6-(2-hydroxyethoxy)-pyridin-3- yl]-2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 228 dec. ¹H NMR(DMSO-d₆): 3.70(m, # 2H); 3.82(s,3H); 4.22(t, 2H); 4.82(m, 1H, exch with D₂O); 6.62(s, 1H); 6.80-6.98(m,3H); 7.24(dd, 1H); 7.53(s, 1H); 7.77(s, 1H); 8.04(m, 1H); 8.49(d, 1H);10.04(s, 1H, exch with D₂O) 11.80(s, 1H, exch with D₂O) 9(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-(2-pyridyloxy-5-pyridyl)-2,4- pentadienamide hydrochloride

H Me H H H H 5Cl 6Cl H 208-210 ¹H NMR(DMSO-d₆): 11.85(s, # 1H); 10.21(s,1H); 8.64(d, 1H); 8.53(s, 1H); 8.52(m, 1H); 8.29(dd, 1H); 7.89(m, 1H);7.76(s, 1H); 7.67(dd, 1H); 7.52(s, 1H); 7.27(dd, 1H); 7.20(d, 1H);6.95(d, 1H); 6.85(d, 1H); 6.64(s, 1H), 3.82(s, 3H) 10 (S,2Z,4E)-5-(5,6-Dichloroindol-2-yl)-N-[2-(1- carbethoxy)-ethoxy-5-pyridyl]-2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 228-230 ¹H NMR(DMSO-d₆): 11.75(s, # 1H); 10.00(s,1H); 8.42(d, 1H); 8.06(dd, 1H); 7.77(s, 1H); 7.52(s, 1H); 7.23(dd, 1H);6.93(d, 1H); 6.90(d, 1H); 6.82(d, 1H); 6.62(s, 1H); 5.19(q, 1H); 4.11(q,2H); 3.81(s, 3H); 1.50(d, 3H); 1.16(t, 3H) 11 (S,2Z,4E)-5-(5,6-Dichloroindol-2-yl)-N-[2-(1- carboxy)ethoxy-5-pyridyl]-2- methoxy-2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 239-240 ¹H NMR(DMSO-d₆): 11.80(s, # 1H); 10.00(s,1H); 8.42(d, 1H), 8.05(dd, 1H); 7.76(s, 1H); 7.52(s, 1H); 7.25(dd, 1H);6.94(d, 1H); 6.87(d, 1H); 6.81(d, 1H); 6.61(s, 1H); 5.18(q. 1H); 3.82(s,3H); 1.50(d, 3H) 12 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N-[6- (1-methyl-ethoxy)pyridin-3-yl]-2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 263 dec. ¹H NMR(DMSO-d₆): 1.28(s, # 6H); 3.82(s,3H); 5.19(m, 1H); 6.62(s, 1H); 6.72-6.98(m, 3H); 7.24(dd, 1H); 7.54(s,1H); 7.77(s, 1H); 8.00(dd, 1H); 8.50(d, 1H); 10.03(s, 1H, exch withD₂O); 11.81(s, 1H, exch with D₂O) 13 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N-(6- dimethylaminopyridin-3-yl)-2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 260-290 ¹H NMR(DMSO-d₆): 3.00(s, # 6H); 3.82(s,3H); 6.61(s, 1H); 6.64(d, 1H); 6.78(d, 1H); 6.91(d, 1H); 7.23(dd, 1H);7.53(s, 1H); 7.76(s, 1H); 7.85 dd, 1H); 8.41(d, 1H); 9.81(s, 1H, exchwith D₂O); 11.78(s, 1H, exch with D₂O) 14 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N-(1- azabicyclo-[3.3.1]nonan-4 beta-yl)-2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 230 ¹H NMR(DMSO-d₆): 1.10-2.25(bm, # 7H),2.60-3.05(m, 6H); 3.73(s, 3H); 4.15(m, 1H); 6.57(s, 1H); 6.59(d, 1H);6.85(d, 1H); 7.17(dd, 1H); 7.51(s, 1H); 7.75(s, 1H); 8.06(d, 1H, exchwith D₂O); 11.76(s, 1H, exch with D₂O) 15 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N-(9- methyl-9- azabicyclo[3.3.1]nonan-3alpha-yl)-2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 293 ¹H NMR(DMSO-d₈): # 0.66-2.15(bm, 10); 2.38(s,3H); 2.84-3.04(m, 2H); 3.71(s, 3H); 4.20(m, 1H); 6.57(s, 1H); 6.63(d,1H); 6.84(d, 1H); 7.17(dd, 1H); 7.51(s, 1H); 7.75(s, 1H); 7.87(d, 1H,exch with D₂O); 11.75(s, 1H,exch with D₂O) 16(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-(8- methyl-8-azabicyclo[3.2.1]oct- 3alpha-yl)-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 262 ¹H NMR(DMSO-d₆): 1.98-2.46(m, # 8H); 2.59(s,3H); 3.74(m, 2H); 3.76(s, 3H), 3.78(m, 1H); 6 58(s, 1H); 6.60(d, 1H);6.88(d, 1H); 7.21(dd, 1H); 7.53(s, 1H); 7.75(s, 1H); 7.95(m, 1H, exchwith D₂O); 11.89(s, 1H, exch with D₂O) 17 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-N-(6-(2- methoxyethoxy)-pyridin-3- yl]-2-methoxy-2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 233 dec ¹H NMR(DMSO-d₆): 11.80(s, 1H, # exch withD₂O); 10.01(s, 1H, exch with D₂O); 8.50(d, 1H); 8.04(dd, 1H); 7.77(s,1H); 7.54(s, 1H), 7.24(dd, 1H); 6.81-6.99(m, 3H); 6.62(s, 1H); 4.34(t,2H); 3.82(s, 3H); 3.64(t, 2H); 3.29(s, 3H). 18 (2Z,4E)-5-[2-(1-Carboxymethyl-5,6- dichloro)indolyl]-2-methoxy-N-[5-(2-methoxypyridinyl]- 2,4-pentadienamide hydrochloride

H Me H H H H 5Cl 6Cl CH2—COOH >250 ¹H NMR(DMSO-d₆): # 10.04(s, 1H);9.01(d, 1H); 8.04(dd, 1H); 7.82(s, 1H); 7.78(s, 1H); 7.60(d, 1H);7.40(s, 1H); 7.26(dd, 1H); 6.86(d, 1H); 6.82(d, 1H); 5.18(s, 2H);3.82(s, 3H) 19 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[6-(2-diethylaminoethoxy)-pyrid- 3-yl]-2-methoxy-2,4- pentadienamidehydrochloride

H Me H H H H 5Cl 6Cl H 201-204 ¹H NMR(DMSO-d₆): 11.86(s, # 1H); 10.10(s,1H); 9.80(s br, 1H); 8.55(d, 1H); 8.11(dd, 1H); 7.76(s, 1H); 7.54(s,1H); 7.26(dd, 1H); 6.95(d, 1H); 6.90(d, 1H); 6.82(d, 1H); 6.61(s, 1H),4.59(t, 2H); 3.83(s, 3H); 3.50(dt, 2H); 3.20(m, 4H); 1.22(t, 6H). 20(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-(1-methylethyl-6-oxopyridin-3-yl)-2- methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 165-168 dec. ¹H NMR(DMSO-d₆): 11.81(s, 1H, # exchwith D₂O); 9.86(s, 1H, exch with D₂O); 8.21(d, 1H); 7.77(s, 1H);7.68(dd, 1H); 7.54(s, 1H); 7.23(dd, 1H); 6.92(d, 1H); 6.81(d, 1H);6.62(s, 1H); 6.40(d, 1H); 5.07(m, 1H); 3.81(s, 3H); 1.28(d, 6H). 21(2Z,4E)-5-(1H-Indol-2-yl)-2- methoxy-N-[4-(2,2,5,6-tetramethyl)-piperidinyl]-2,4- pentadienamide hydrochloride

H Me H H H H H H H >250 ¹H NMR(DMSO-d₆): 11.41(s, # 1H); 9.09(d br, 1H);8.19(d, 1H); 8.01(d br, 1H); 7.49(d, 1H); 7.32(d, 1H), 7.12(dd, 1H);7.11(dd, 1H); 6.97(dd, 1H); 6.85(d, 1H); 6.65(d, 1H); 6.56(s, 1H);4.22(m, 1H); 3.71(s, 3H); 1.85(dd, 1H); 1.65(dd, 1H); 1.43(s, 6H);1.41(s, 6H). 22 (2Z,4E)-5-(5,6-Dichloro-3- ethyl-1H-indol-2-yl)-2-methoxy-N-[4-(2,2,6,6- tetramethyl)piperidinyl]-2,4- pentadienamidehydrochloride

H Me H H H Et 5Cl 6Cl H >250 ¹H NMR(DMSO-d₆): 11.52(s, # 1H), 9.00(d br,1H); 8.20(d, 1H), 7.99(d br, 1H), 7.75(s, 1H); 7.46(s, 1H); 7.13(dd,1H); 6.98(d, 1H); 6.70(d, 1H); 4.12(m, 1H); 3.71(s, 3H); 2.78(m, 2H);1.85(d br, 2H); 1.61(dd br, 2H); 1.44(s, 6H); 1.40(s, 6H); 1.13(t, 3H).23 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[6-(2-dimethylaminoethylamino)- pyrid-3-yl]-2-methoxy-2,4- pentadienamidehydrochloride

H Me H H H H 5Cl 6Cl H >250 ¹H NMR(DMSO-d₆ + TFA): # 11.86(s, 1H);10.32(s, 1H); 10.05(s br, 1H); 8.55(d, 1H); 8.26(dd, 1H); 7.75(s, 1H);7.53(s, 1H); 7.26(dd, 1H); 7.16(d, 1H); 6.96(d, 1H); 6.88(d, 1H);6.62(s, 1H); 3.82(s, 3H); 3.79(t, 2H); 3.36(t br, 2H); 2.85(s, 6H). 24(2Z,4E)-5-[(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-[3-piperazin-1-yl)-propyl]-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 200 ¹H NMR(DMSO-d₆): 1.61(m, # 2H); 2.19-2.43(m,6H); 2.80(m, 4H); 3.20(m, 2H); 3.72(s, 3H); 6.57(s, 1H); 6.64(d, 1H);6.85(d, 1H); 7.17(dd, 1H); 7.52(s, 1H); 7.75(s, 1H); 8.27(t, 1H, exchwith D₂O); 11.79(s, 1H, exch with D₂O). 25 (2Z,4E)-5-(5,6-Dichloro-1-methylindol-2-yl)-2- methoxy-N-[4-(2,2,6,6-tetramethyl)piperidinyl]-2,4- pentadienamide

H Me H H H H 5Cl 6Cl Me 210-213 ¹H NMR(DMSO): 7.90(m br, # 1H); 7.80(s,1H); 7.74(s, 1H); 7.19(dd, 1H), 7.05(d, 1H); 6.93(s, 1H); 6.67(d, 1H);4.19(m br, 1H); 3.79(s, 3H); 3.71(s, 3H); 1.65(m, 2H); 1.20(m, 2H);1.20(s, 6H); 1.09(s, 6H). 26 (2Z,4E)-5-(5- Trifluoromethylindol-2-yl)-2-methoxy-N-[4-(2,2,6,6- tetramethyl)piperidinyl]-2,4- pentadienamidehydrochloride

H Me H H H H 5CF₃ H H >250 ¹H NMR(DMSO-d₆): 11.90(s, # 1H); 8.99(d br,1H); 8.23(d, 1H); 7.96(d br, 1H); 7.89(s, 1H); 7.50(d, 1H); 7.49(d, 1H);7.21(dd, 1H); 6.90(d, 1H); 6.72(s, 1H); 6.64(d, 1H); 4.23(m, 1H);3.71(s, 3H), 1.88(d br, 2H); 1.62(dd br, 2H); 1.42(s, 6H); 1.40(s, 6H).27 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-(3,7-dimethyl-3,7- diazabicyclo[3.3.1]nonan-9- yl)-2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 200 ¹H NMR(DMSO-d₆): 2.26(m, # 2H); 2.39(s, 3H);2.53(s, 3H); 2.66-3.33(m, 8H); 3.76(s, 3H); 3.88(m, 1H); 6.58(s, 1H);6.64(d, 1H); 6.87(d, 1H); 7.20(dd, 1H); 7.53(s, 1H); 7.75(s, 1H);8.12(d, 1H, exch with D₂O); 11.88(s, 1H, exch with D₂O). 28Exo-(2Z,4E)-5-(5,6- Dichloro-1H-indol-2-yl)-2- methoxy-N-[(8-methyl-8-azabicyclo[3.2.1]oct-3- yl)methyl]-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 255 ¹H NMR(DMSO-d₆): 1.10-1.98(m, # 9H); 2.13(s,3H); 2.97(bs, 2H); 3.22(m, 2H); 3.70(s, 3H); 6.57(s, 1H); 6.63(d, 1H);6.84(d, 1H); 7.16(dd, 1H); 7.51(s, 1H); 7.74(s, 1H); 8.24(t, 1H, exchwith D₂O); 11.76(s, 1H, exch with D₂O). 29 Endo-(2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2- methoxy-N-[(8-methyl-8-azabicyclo[3.2.1]oct-3- yl)methyl]-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 180-198 ¹H NMR(DMSO-d₆): 1.16-2.03(m, # 9H),2.12(s, 3H); 2.98(m, 2H); 3.22(m, 2H); 3.70(s, 3H); 6.57(s, 1H); 6.62(d,1H); 6.84(d, 1H); 7.16(dd, 1H); 7.51(s, 1H); 7.74(s, 1H); 8.24(t, 1H,exch with D₂O); 11.75(s, 1H, exch with D₂O). 30(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-(1,2,3,4- tetrahydro-2,4-dioxopyrimidin-5-yl)-2- methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H >330 ¹H NMR(DMSO-d₆): 3.85(s, # 3H); 6.61(s, 1H);6.84(d, 1H); 6.96(d, 1H); 7.21(dd, 1H); 7.52(s, 1H); 7.76(s, 1H);8.10(s, 1H); 8.69(s, 1H, exch with D₂O); 11.25(bm, 2H, exch with D₂O);11.80(s, 1H, exch with D₂O). 31 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N- (2alpha-hydroxy-8-methyl)-8-azabicyclo[3.2.1]oct- 3beta-yl)-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 290 ¹H NMR(DMSO-d₆): 1.53-2.25(m, # 6H), 2.58(s,3H); 3.42-3.85(m, 3H); 3.73(s, 3H); 3.94(m, 1H); 5.33(bs, 1H, exch withD₂O); 6.57(s, 1H); 6.63(d, 1H); 6.85(d, 1H); 7.19(dd, 1H); 7.52(s, 1H);7.74(s, 1H); 8.02(d, 1H, exch with D₂O); 11.82(bs, 1H, exch with D₂O).32 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-[2-(1-methylethoxy)-pyrimidin- 5-yl]-2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 253-254 ¹H NMR(DMSO-d₆): 1.31(d, # 6H); 3.83(s,3H); 5.16(m, 1H); 6.64(s, 1H); 6.87(d, 1H); 6.98(d, 1H); 7.25(dd, 1H);7.54(s, 1H); 7.77(s, 1H), 8.87(s, 2H); 10.21(bs, 1H, exch with D₂O);11.82(bs, 1H, exch with D₂O). 33 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N-[5- (dimethylamino- methyleneamino)pyrimidin-2-yl)-2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 275 ¹H NMR(DMSO-d₆): 2.95(s, # 3H); 3.05(s, 3H);3.81(s, 3H); 6.62(s, 1H); 6.78(d, 1H); 6.92(d, 1H); 7.23(dd, 1H);7.53(s, 1H); 7.76(s, 1H); 7.94(s, 1H); 8.33(s, 2H); 10.12(s, 1H, exchwith D₂O); 11.80(bs, 1H, exch with D₂O) 34 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N-(8- phenyl-8- azabicyclo[3.2.1]oct-3beta-yl)-2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 233 ¹H NMR(DMSO-d₆): 1.42-2.08(m, # 8H); 3.62(s,3H); 4.16-4.46(m, 3H); 6.49-6.68(m, 3H); 6.73-6.88(m, 3H); 7.02-7.27(m,3H); 7.49(s, 1H); 7.74(s, 1H); 7.98(d, 1H, exch with D₂O); 11.71(bs, 1H,exch with D₂O). 35 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N-(2- dimethyl-aminopyrimidin-5-yl)-2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 299 ¹H NMR(DMSO-d₆): 3.10(s, # 6H); 3.82(s, 3H);6.62(s, 1H); 6.83(d, 1H); 6.93(d, 1H); 7.24(dd, 1H); 7.53(s, 1H);7.76(s, 1H); 8.62(s, 2H); 9.93(s, 1H, exch with D₂O); 11.80(bs, 1H, exchwith D₂O). 36 (2Z,4E)-N-(2- Acetylaminopyrimidin-5-yl)-5-(5,6-dichloro-1H-indol-2- yl)-2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 307 ¹H NMR(DMSO-d₆): 2.15(s, # 3H); 3.84(s, 3H);6.64(s, 1H); 6.89(d, 1H); 6.98(d, 1H); 7.25(dd, 1H); 7.54(s, 1H);7.77(s, 1H); 8.98(s, 2H); 10.29(s, 1H, exch with D₂O); 10.54(s, 1H, exchwith D₂O); 11.82(bs, 1H, exch with D₂O). 37 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-N-[2-(1H- imidazol-4-yl)ethyl]-2- methoxy-2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 140 ¹H NMR(DMSO-d₆): 2.71(t, # 2H); 3.40(q, 2H);3.70(s, 3H); 6.58(s, 1H); 6.65(d, 1H); 6.85(s, 1H), 6.86(d, 1H);7.16(dd, 1H); 7.52(s, 1H); 7.61(s, 1H); 7.75(s, 1H); 8.27(t, 1H, exchwith D₂O); 11.76(bs, exch with D₂O). 38 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-N-[3- [(tricyclo[3.3.1.1.(3,7)]-dec- 1-yl)amino]propyl]-2-methoxy-2,6- pentadienamide

H Me H H H H 5Cl 6Cl H 220 ¹H NMR(DMSO-d₆) 1.57(m, # 14H); 1.21(m, 3H);1.92(t, 2H), 1.16(q, 2H); 3.84(s, 3H); 6.58(s, 1H); 6.65(d, 1H); 6.85(d,1H); 7.17(dd, 1H); 7.51(s, 1H); 7.75(s, 1H); 8.53(t, 1H, exch with D₂O);11.76(bs, 1H, exch with D₂O). 39 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N-(5- pyrimidinyl)-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 293 ¹H NMR(DMSO-d₆): 3.85(s, # 3H); 6.65(s, 1H);6.92(d, 1H); 7.00(d, 1H); 7.27(dd, 1H); 7.55(s, 1H); 7.78(s, 1H);8.92(s, 1H); 9.17(s, 2H); 10.41(s, 1H, exch with D₂O); 11.83(bs, 1H,exch with D₂O). 40 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N-(2- phenyl-5-pyrimidinyl)-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 299 ¹H NMR(DMSO-d₆): 3.87(s, # 3H); 6.66(s, 1H);6.94(d, 1H), 7.01(d, 1H); 7.28(dd, 1H); 7.46-7.60(m, 4H); 7.78(s, 1H);8.36(m, 2H), 9.28(s, 2H); 10.49(s, 1H, exch with D₂O); 11.85(bs, 1H,exch with D₂O). 41 (2Z,4E)-N-(2-Amino-5- pyrimidinyl)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy- 2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 305 ¹H NMR(DMSO-d₆): 11.80(bs, 1H, # exch withD₂O); 9.87(s, 1H, exch with D₂O); 8.50(s, 2H); 7.77(s, 1H); 7.54(s, 1H);7.24(dd, 1H); 6.94(d, 1H); 6.81(d, 1H); 6.63(s, 1H); 6.53(s, 2H, exchwith D₂O); 3.81(s, 3H). 42 (2Z,4E)-5-[(5,6-Dichloro-1H-indol-2-yl)-N-[3-[4-(4- benzoyl)benzoylpiperazin-1-yl]propyl]-2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 198-200 ¹H NMR(DMSO-d₆): 11.70(s, # 1H); 8.19(t,1H); 7.80-7.71(m, 5H); 7.70(dd, 1H), 7.60-7.51(m, 5H); 7.17(dd, 1H);6.84(d, 1H); 6.63(d, 1H); 6.59(s, 1H); 3.71(s, 3H); 3.65(m, 2H); 3.33(m,2H); 3.22(dt, 2H); 2.60-2.30(m, 6H); 1.66(m, 2H). 43(2Z,4E)-5-(5,6-Dichloro-1H- indo-2-yl)-N-(2-cyano-5-pyrimidinyl)-2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 292 ¹H NMR(DMSO-d₆): 11.84(bs, # 1H, exch withD₂O); 10.54(s, 1H), exch with D₂O); 9.15(s, 2H); 7.78(s, 1H); 7.55(s,1H); 7.27(dd, 1H); 7.01(d, 1H); 6.93(d, 1H), 6.66(s, 1H); 3.85(s, 3H).44 (2Z,4E)-5-(1H-indol-2-yl)-N- (3-diethylaminopropyl)-2- methoxy-2,4-pentadienamide

H Me H H H H H H H 134-137 ¹H NMR(DMSO-d₆): 11.40(s, # 1H); 8.23(t br,1H); 7.48(d, 1H); 7.31(d, 1H); 7.14(dd, 1H); 7.10(dd, 1H); 6.96(dd, 1H);6.84(d, 1H); 6.66(d, 1H); 6.55(s, 1H); 3.76(s, 3H); 3.25(m, 2H); 2.52(m,6H); 1.63(m, 2H); 1.00(t, 6H). 45 (2Z,4E)-5-(1H-indol-2-yl)-2-methoxy-N-(1,2,2,6,6- pentamethyl-piperidin-4-yl)- 2,4-pentadienamide

H Me H H H H H H H 198-201 ¹H NMR(DMSO-d₆): 11.40(s, # 1H); 7.81(d br,1H); 7.47(d, 1H); 7.32(d, 1H); 7.12(dd, 1H); 7.00(dd, 1H); 6.96(dd, 1H);6.81(d, 1H); 6.61(d, 1H); 6.55(s, 1H); 4.09(m, 1H); 3.70(s, 3H); 2.20(s,3H), 1.62(d br, 2H); 1.46(dd br, 2H); 1.09(s, 6H); 1.02(s, 6H). 46 Ethyl(2Z,4E)-5-(5,6- Dichloro-1H-indol-2-yl)-[(2- methoxy-penta-2,4-dienoyl)amino]-2- azabicyclo[2.2.2]octane-2- carboxylate

H Me H H H H 5Cl 6Cl H 168-170 ¹H NMR(DMSO-d₆): 1.10-1.28(m, # 3H);1.38-2.23(m, 7H); 3.09-3.59(m, 2H); 3.71 and 3.73(2s, 3H); 3.85-4.12(m,4H); 6.58(s, 1H); 6.60(d, 1H); 6.85(d, 1H); 7.18(dd, 1H); 7.52(s, 1H);7.75(s, 1H); 8.17(2d, 1H, exch with D₂O); 11.75(s, broad, 1H, exch withD₂O) 47 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-(1,2,6-trimethylpiperidin-4- yl)-2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 217 ¹H NMR(DMSO-d₆): 1.04(d, # 6H); 1.32(m, 2H);1.65(m, 2H); 1.96-2.21(m, 2H); 2.12(s, 3H); 3.70(s, 3H); 3.74(m, 1H);6.57(s, 1H); 6.60(d, 1H); 6.84(d, 1H); 7.17(dd, 1H); 7.51(s, 1H);7.75(s, 1H); 7.96(d, 1H, exch with D₂O); 11.75(s, 1H, exch with D₂O) 48(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N- [2-[4-(2-methoxy-phenyl)piperazin-1- yl]ethyl] 2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 227-229 ¹H NMR(DMSO-d₆): 2.45-2.60(m, # 6H);2.96(m, 4H); 3.25-3.35(m, 2H); 3.74(s, 3H); 3.77(s, 3H); 6.59(s, 1H);6.66(d, 1H); 6.85(d, 1H); 6.84-6.97(m, 4H); 7.18(dd, 1H); 7.51(s, 1H);7.74(s, 1H); 8.01(t br, 1H); 11.7(s br, 1H). 49(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-(8a betaH-5 alpha-methyl-octahydroindolizin-7alpha- yl)-2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 231 ¹H NMR(DMSO-d₆): 11.74(s, # broad band, 1Hexch with D₂O); 8.00(d, 1H exch with D₂O); 7.74(s, H); 7.51(s, 1H),7.17(dd, 1H); 6.84(d, 1H); 6.60(d, 1H); 6.57(s, 1H); 3.74(m, 1H);3.70(s, 3H); 3.08(m, 1H); 1.50-2.14(m, 8H); 1.13-1.42(m, 3H); 1.03(d,3H) 50 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-H-[1-(2-hydroxyethylpiperidin-4- yl)-2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 218 ¹H NMR(DMSO-d₆): 11.73(s, # broad band, 1H,exch with D₂O); 7.95(d, 1H exch with D₂O); 7.75(s, 1H); 7.51(s, 1H);7.17(dd, 1H); 6.83(d, 1H); 6.60(d, 1H); 6.57(s, 1H); 4.35(t, 1H exchwith D₂O); 3.71(s, 3H); 3.62(m, 1H); 3.48(q, 2H); 2.84(m, 2H); 2.36(t,2H); 2.00(m, 2H); 1.43-1.74(m, 4H) 51 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-N-[1-(2,3- dihydroxypropyl)piperidin- 4-yl)-2-methoxy-2,4-pentadienamide hydrochloride

H Me H H H H 5Cl 6Cl H 275 ¹H NMR(DMSO-d₆): 11.8(s, broad # band, 1Hexch with D₂O); 9.49(broad band, 2H, exch with D₂O), 8.29(d, 1H exchwith D₂O); 7.75(s, 1H ar); 7.52(s, 1H); 7.20(dd, 1H); 6.85(d, 1H);6.65(d, 1H); 6.58(s, 1H); 5.53(d, 1H, exch with D2O); 4.98(m, 1H);4.36(m, 1H); 3.93(m, 2H); 3.73(s, 3H); 2.87-3.62(m, 6H); 1.94(m, 4H) 52Ethyl (2Z,4E)-[(4-[5-(5,6- Dichloro-1H-indol-2-yl)-2- methoxy-penta-2,4-dienoyl]amino]- piperidineacetate

H Me H H H H 5Cl 6Cl H 237 ¹H NMR(DMSO-d₆): 11.75(s, broad # band, 1H,exch with D₂O); 7.99(d, 1H, exch with D₂O); 7.75(s, 1H); 7.52(s, 1H);7.17(dd, 1H); 6.85(d, 1H); 6.61(d, 1H); 6.58(s, 1H); 4.09(q, 2H);3.72(s, 3H); 3.65(m, H); 3.19(s, 2H); 2.83(m, 2H); 2.22(m, 2H);1.46-1.75(m, 4H); 1.19(t, 3H) 53 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-N-[8-(2- acetyloxyethane)-8- azabicyclo[3.2.1]oct-3beta-yl]2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 118-120 ¹H NMR(DMSO-d₆): 11.7(s, broad # band 1Hexch with D₂O); 7.9(d, 1H, exch with D₂O); 7.75(s, 1H), 7.51(s, 1H);7.16(dd, 1H); 6.83(d, 1H); 6.60(d, 1H); 6.56(s, 1H); 4.06(m, 3H);3,69(s, 3H), 3.23(m, H); 2.65(t, 2H); 2.02(s, 3H), 5.81-1.96(m, 8H) 54(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-(2a beta, 4a alpha, 6 alpha,7a alpha- decahydro-pyrrolo[2.1.5- cd]indolizyn-6-yl)-2- methoxy-2.4-pentadienamide

H Me H H H H 5Cl 6Cl H 226 ¹H NMR(DMSO-d₆): 11.75(s, # broad band, 1Hexch with D₂O); 7.91(d, 1H, exch with D₂O); 7.75(s, 1H ar); 7.51(s, 1Har); 7.17(dd, 1H); 6.84(d, 1H); 6.61(d, 1H); 6.57(s, 1H); 3.73(m, 1H);3.70(s, 3H); 3 08(m, 3H); 5.26(m, 2H); 1.04-1.81(m, 10H) 55(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-(2a beta, 4a alpha, 6 beta, 7aalpha- decahydro-pyrrolo[2.1.5- cd]indolizyn-6-yl)-2- methoxy-2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 238 ¹H NMR(DMSO-d₆): 11.7(s, broad # band, 1H,exch with D₂O); 7.75(s, 1H); 7.62(d, 1H exch with D₂O); 7.52(s, 1H);7.19(dd, 1H); 6.85(d, 1H); 6.60(d, 1H); 6.58(s, 1H); 4.04(m, 1H);3.76(s, 3H); 3.24(m, 3H); 1.00(m, 2H); 1.03-1.85(m, 10H) 56(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[8-(2-ethanol)-8-azabicyclo[3.2.1]oct- 3beta-yl]2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 267-270 ¹H NMR(DMSO-d₆): 11.79(s, broad # band,1H exch with D₂O); 7.92(d, 1H exch with D₂O); 7.74(s, 1H), 7.52(s, 1H);7.17(dd, 1H); 6.83(d, 1H); 6.59(d, 1H); 6.57(s, 1H); 4.34(m, 1H, exchwith D₂O); 4.03(m, 1H); 3.69(s, 3H), 3.45(m, 2H); 3.21(m, 2H); 2.48(t,2H), 1.40-1.97(m, 8H) 57 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N-(2 alpha, 6 beta 9a alpha)-octahydro-6-methyl-2H- quinolizin-2-yl]-2,4- pentadienamide

H Me H H H H 5Cl 5Cl H 200-202 ¹H NMR(DMSO-d₆): 11.79(s, # 1H); 7.74(s,1H); 7.73(s, 1H); 7.54(s, 1H); 7.13(dd, 1H); 6.84(d, 1H); 6.60(m, 2H),3.95(s, 1H); 3.73(s, 3H); 3.11(m, 1H); 2.60-2.15(m, 3H); 1.90-1.15(m,10H); 1.08(d, 3H). 58 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N- [1,2,6-trimethylpiperidin-4-yl]-2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 214 ¹H NMR(DMSO-d₆): 11.74(s, # broad band, 1H);7.90(d, 1H); 7.74(s, 1H); 7.51(s, 1H); 7.17(dd, 1H); 6.83(d, 1H);6.60(d, 1H); 6.56(s, 1H); 4.01(m, 1H); 3.70(s, 3H); 3.05(m, 1H); 2.52(m,1H); 2.18(s, 3H); 1.85-1.1(m, 4H); 0.96(2d, 6H). 59(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[1-(2- hydroxyethyl)-2,6-dimethylpiperidin-4-yl]-2- methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 150 ¹H NMR(DMSO-d₆): 11.75(s, broad # band, 1H);7.93(d, 1H), 7.75(s, 1H); 7.51(s, 1H); 7.16(dd, 1H); 6.84(d, 1H);6.60(d, 1H); 6.57(s, 1H); 4.38(s, broad band, 1H); 3.70(s, 3H); 3.36(t,2H); 2.80-2.30(m, 5H); 1.77-1.49(m, 2H); 1.38-1.10(m, 2H); 1.05(d, 6H).60 (2Z,4E)-5-(5-Bromo-1H- indol-2-yl)-N-2-methoxy-(1,2,2,6,6-pentamethyl- piperidin-4-yl)-2,4- pentadienamide

H Me H H H H 5Br H H 225-226 ¹H NMR(DMSO-d₆): 11.61(s, br, # 1H);7.83(d, 1H); 7.68(d, 1H), 7.29(d, 1H); 7.19(dd, 1H); 7.15(dd, 1H);6.82(d, 1H); 6.59(d, 1H); 6.55(d, 1H); 4.15-4.02(m, 1H); 3.71(s, 3H);2.18(s, 3H); 1.62(dd, 2H); 1.44(dd, 2H); 1.08(s, 6H); 1.02(s, 6H). 61(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-(3- dimethylamino-cyclohexyl)-2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 200-201 ¹H NMR(DMSO-d₆): 11.75(s, # broad band,1H); 7.80(s, broad band, 1H); 7.75(s, 1H); 7.51(s, 1H); 7.17(dd, 1H);6.83(d, 1H); 6.59(d, 1H); 6.57(s 1H), 4.06(m, 1H); 3.71(s, 3H);2.30-2.20(m, 1H); 2.16(s, 6H); 2.45-1.05(m, 8H). 62(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[3-[2,6- dimethyl-4-(2-pyrimidinyl)plperazin-1- yl]propyl]-2-methoxy-2,4- pentadienamidehydrochloride

H Me H H H H 5Cl 6Cl H 245 ¹H NMR(DMSO-d₆): 11.80(s, # broad band, 1H);10.40(s, broad band, 1H), 8.43(d, 2H); 8.39(m, 1H); 7.76(s, 1H); 7.53(s,1H); 7.19(dd, 1H); 6.87(d, 1H); 6.76(t, 1H); 6.69(d, 1H); 6.59(s, 1H);4.74(m, 2H); 3.74(s, 3H); 3.50-3.00(m, 8H); 1.82(m, 2H); 1.35(d, 6H). 63(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-[3-[-4-(2-methoxyphenyl)- piperazin-1-yl]propyl]2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 181-182 ¹H NMR(DMSO-d₆): 11.72(s br, # 1H);8.25(t, 1H); 7.72(s, 1H); 7.50(s, 1H); 7.18(dd, 1H); 6.98-6.81(m, 5H);6.64(d, 1H); 6.58(s, 1H); 3.76(s, 3H); 3.73(s, 3H); 3.27(dt, 2H);2.99(m, 4H); 2.50(m, 4H); 2.39(t, 2H); 1.73-1.62(m 2H). 64(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-(3-[-4-(phenyl)piperazin-1- yl]propyl] 2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 223-225 ¹H NMR(DMSO-d₆): 11.75(s br, # 1H);8.26(t, 1H); 7.74(s, 1H); 7.51(s, 1H); 7.20(dd, 2H); 7.17(dd, 1H);6.92(d, 2H); 6.84(d, 1H); 6.79(dd, 1H); 6.65(d, 1H); 6.57(d, 1H);3.73(s, 3H); 3.26(dt, 2H); 3.13(m, 4H); 2.50(m, 4H); 2.39(t, 2H);1.73-1.62(m, 2H). 65 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-4- methyl-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)- 2,4-pentadienamide

H Me H Me H H 5Cl 6Cl H 131-132 ¹H NMR(DMSO-d₆): 11.35(s, br, # 1H);7.89(d, 1H); 7.78(s, 1H); 7.56(s,1H); 6.73(s, 1H); 6.62(s, 1H), 6.37(s,1H); 4.15-4.00(m, 1H); 3.60(s, 3H); 2.29(s, 3H); 2.18(s, 3H); 1.62(dd,2H); 1.43(dd, 2H); 1.09(s, 6H); 1.02(s, 6H). 66(2Z,4E)-5-(5,8-Dichloro-1H, indol-2-yl)-N-[3- (dimethylamino)propyl]-2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 181-183 ¹H NMR(DMSO-d₆): 11.71(s br, # 1H);8.25(t, 1H); 7.73(s, 1H); 7.51(s, 1H); 7.18(dd, 1H); 6.83(d, 1H);6.64(d, 1H); 6.58(s, 1H); 3.76(s, 3H); 3.70(s, 3H); 3.20(dt, 2H),2.24(t, 2H); 2.13(s, 6H); 1.66-1.56(m, 2H). 67(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[(3- dimethylamino)phenyl]-2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 140-141 ¹H NMR(DMSO-d₆): 11.78(s br, # 1H);9.70(s, 1H); 7.76(s, 1H); 7.52(s, 1H); 7.23(dd, 1H); 7.20-7.08(m, 3H);6.91(d, 1H); 6.77(d, 1H); 6.61(s, 1H); 6.48(d br, 1H); 3.81(s, 3H);2.89(s, 6H). 68 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[3-[-4-(3-chlorophenyl)piperazin-1- yl]propyl]-2-methoxy-2,4 pentadienamide

H Me H H H H 5Cl 6Cl H 192-193 ¹H NMR(DMSO-d₆): 11.73(s br, # 1H);8.24(t, 1H); 7.74(s, 1H), 7.50(s, 1H); 7.20(dd, 2H); 7.16(dd, 1H);6.95-8.88(m, 2H); 6.83(d, 1H); 6.78(d, 1H); 6.63(d, 1H); 6.58(s, 1H);3.70(s, 3H); 3.26(dt, 2H); 3.18(m, 4H); 2.50(m, 4H); 2.39(t, 2H);1.72-1.63(m, 2H). 69 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-N-[3-[-4-(4- chlorophenyl)piperazin-1-yl]propyl]-2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 218-219 ¹H NMR(DMSO-d₆): 11.72(s br, # 1H);8.23(t, 1H); 7.73(s, 1H); 7.50(s, 1H); 7.21(d, 2H); 7.16(dd, 1H);6.93(d, 2H); 6.84(d, 1H); 6.64(d, 1H); 6.58(s, 1H); 3.73(s, 3H);3.24(dt, 2H); 3.11(m, 4H); 2.50(m, 4H); 2.39(t, 2H); 1.71-1.62(m, 2H).70 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[3-[-4-(2-chlorophenyl)piperazin-1- yl]propyl]-2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 193-194 ¹H NMR(DMSO-d₆): 11.71(s, # 1H); 8.23(t,1H); 7.74(s, 1H); 7.51(s, 1H); 7.40(dd, 1H); 7.29(ddd, 1H); 7.16(dd,1H); 7.15(dd, 1H); 7.02(ddd, 1H); 6.85(d, 1H); 6.65(d, 1H), 6.59(s, 1H);3.74(s, 3H); 3.25(dt, 1H); 3.00(m, 4H); 2.55(m, 4H); 2.40(t, 2H);2.22-2.13(m, 2H). 71 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[3-(dibutylamino)propyl]-2- methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 144-146 ¹H NMR(DMSO-d₆) 11.72(s br, # 1H);8.18(t, 1H); 7.74(s, 1H); 7.51(s, 1H); 7.17(dd, 1H); 6.84(d, 1H);6.63(d, 1H); 6.58(s, 1H); 3.72(s, 3H); 3.18(dt, 2H); 2.40-2.31(m, 6H),1.63-1.54(m, 2H); 1.40-1.21(m, 8H); 0.87(t, 6H). 72(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[3-[-4-(2,6-dimethylphenyl)piperazin- 1-yl]propyl]-2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 228-230 ¹H NMR(DMSO-d₆): 11.71(s br, # 1H);8.20(t, 1H); 7.74(s, 1H); 7.52(s, 1H); 7.17(dd, 1H); 6.97-6.89(m, 3H);6.85(d, 1H), 6.65(d, 1H); 6.58(s, 1H); 3.75(s, 3H); 3.25(dt, 2H);3.02(m, 4H); 2.47(m, 4H); 2.39(t, 2H); 2.27(s, 6H); 1.73-1.63(m, 2H). 73(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-[3-(pyrrolidin-2-one)propyl]- 2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 165-167 ¹H NMR(DMSO-d₆): 11.79(s br, # 1H);8.14(t, 1H); 7.74(s, 1H); 7.52(s, 1H); 7.18(dd, 1H); 6.85(d, 1H);6.66(d, 1H); 6.58(s, 1H); 3.75(s, 3H); 3.34(t, 2H); 3.20(t, 2H);3.14(dt, 2H); 2.22(t, 2H); 1.97-1.87(m, 2H); 1.69-1.60(m, 2H). 74(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[3-[4-(2-pyrimidinyl)homopiperazin- 1-yl]propyl]-2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 220-222 ¹H NMR(DMSO-d₆) 11.71(s, # 1H); 8.32(d,2H); 8.17(t br, 1H); 7.74(s, 1H); 7.51(s, 1H), 7.16(dd, 1H); 6.84(d,1H); 6.63(d, 1H); 6.57(s br, 1H); 6.55(dd, 1H); 3.83-3.77(m, 2H);3.74(t, 2H); 3.72(s, 3H); 3.19(dt, 2H); 2.73-2.66(m, 2H); 2.58-2.51(m,2H); 2.45(t, 2H); 1.88-1.77(m, 2H); 1.67-1.55(m, 2H). 75(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[3-[4-(2- pyridyl)piperazin-1-yl]propyl]-2-methoxy-2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 219-220 ¹H NMR(DMSO-d₆): 11.80(s br, # 1H);8.25(t br, 1H); 8.10(dd, 1H); 7.72(s, 1H); 7.51(s, 1H); 7.51(ddd, 1H);7.19(dd, 1H); 6.82(d, 1H); 6.80(d, 1H); 6.64(d, 1H); 6.61(dd, 1H);6.58(s, 1H); 3.71(s, 3H); 3.46(m, 4H); 3.23(dt, 2H); 2.46(m, 4H);2.39(t, 2H), 1.73-1.63(m, 2H). 76 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N-[3- [-4-(3-methoxyphenyl)- piperazin-1-yl]-propyl] 2,4- pentadienamide

H Me H H H H 5Cl 6Cl H 172-173 ¹H NMR(DMSO-d₆) 11.70(s br, # 1H); 8.25(tbr, 1H), 7.72(s, 1H); 7.50(s, 1H); 7.16(dd, 1H); 7.10(dd, 1H); 6.84(d,1H); 6.64(d, 1H); 6.57(s, 1H); 6.52(dd, 1H); 6.44(dd, 1H); 6.36(dd, 1H);3.72(s, 3H); 3.24(dt, 2H); 3.13(m, 4H); 2.50(m, 4H); 2.40(t br, 2H);1.73-1.64(m, 2H). 77 (2Z,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N-[3- [-4-(4-methoxyphenyl)-piperazin-1-yl]propyl]2,4-pentadienamide

H Me H H H H 5Cl 6Cl H 197-199 ¹H NMR(DMSO-d₆): 11.70(s br, # 1H);8.25(t br, 1H), 7.74(s, 1H); 7.51(s, 1H); 7.16(dd, 1H); 6.88-680(ABq,4H); 6.84(d, 1H); 6.65(d, 1H), 6.57(s br, 1H), 3.73(s, 3H); 3.67(s, 3H);3.25(dt, 2H); 3.02(m, 4H); 2.51(m, 4H); 2.39(t, 2H); 1.72-1.63(m, 2H)

List of Abbreviations Used in the Above Preparations and Examples

[0352] Florisil Registered trademark Celite Registered trade mark fordicalite DMF Dimethylformamide EI Electron Impact AcOEt Ethyl acetateFAB POS Fast Atom Bombardment/Positive ions detection MS Mass SpectrumTHE Tetrahydrofuran TSP ThemoSpray

[0353] Biological Assays

[0354] Background. It is known that, upon attachment to bone, anelectrogenic H⁺-adenosine triphosphatase (ATPase) is polarised to theosteoclast-bone interface. The pump transports massive quantities ofprotons into the resorption microenvironment to effect mobilisation ofthe bone mineral and to create the acidic pH required by collagenases todegrade the bone matrix.

[0355] The vacuolar nature of the osteoclast proton pump was originallyrecognised by Blair [H. C. Blair at al., Science, 245, 855 (1989)] andthan confirmed by Bekker [P. J. Bekker et al., J. Bone Min. Res., 5, 569(1990)] and V{umlaut over (aa)}nänen [K. K. V{umlaut over (aa)}nänen etal., J. Cell. Biol., 111, 1305 (1990)]. Evidence was based uponpreparations of ruffled membrane fragments from avian osteoclasts(obtained from the medullar bone of calcium-starved egg-laying hens).The resulting membrane vesicles acidify in response to ATP, which iseasily assessed by measuring the fluorescence quench of acridine orange,a weak base which accumulates into acidic compartments.

[0356] The biochemical pattern indicated that the osteoclast proton pumpbelonged to the vacuolar-like ATPases since proton transport wasinhibited by N-ethylmaleimide (NEM), a sulphydryl reagent, and bybafilomycin A₁, a selective inhibitor of vacuolar H⁺-ATPases [J. E.Bowman et al., Proc. Natl. Acad. Sci. USA, 85, 7972 (1988)], whilst itwas not inhibited by ouabain, an inhibitor of Na⁺/K⁺-ATPases; sodiumorthovanadate, an inhibitor of p-ATPases, or by omeprazole or SCH 28080,both of which are inhibitors of gastric H⁺/K⁺-ATPase [J. P. Mattson etal., Acta Physiol. Scand., 146, 253 (1992)].

[0357] It is known that specific inhibitors of vacuolar ATPases, such asbafilomycin A₁, are able to inhibit bone resorption in osteoclastcultures [K. Sundquist et al., Biochem. Biophys. Res. Commun. 168,309-313 (1990)]

[0358] Inhibition of Proton Transport and v-ATPase Activity in MembraneVesicles

[0359] Preparation of Crude Bone Microsomes from Calcium-StarvedEgg-Laying Hens.

[0360] Vesicles were prepared from medullar bone obtained from tibiaeand femurs of egg-laying hens which were calcium-starved for at least 15days. Briefly, bone fragments were scraped with a 24 scalpel blade,suspended in 40 ml of isolation medium (0.2 M sucrose, 50 mM KCl, 10 mMHepes, 1 mM EGTA, 2 mM dithiotheitrol, pH 7.4) and filtered through a100 μm pore size nylon mesh. The whole procedure was performed at 4° C.After homogenisation in a potter (20 strokes) in 40 ml of isolationmedium an initial centrifugation (6,500×g_(max)×20 min) was performed toremove mitochondria and lysosomes. The supernatant was centrifuged at100,000×g_(max) for 1 hr and the pellet was collected in 1 ml ofisolation medium, divided into 200 μl aliquots, immediately frozen inliquid nitrogen and stored at −80° C. The protein content was determinedusing a Biorad colourimetric kit according to Bradford [M. Bradford,Anal. Biochem., 72, 248 (1976)]. For the proton transport assay, 5-10 μlof membranes were used.

[0361] Purification of osteoclast membranes. 1 ml of crude microsomalvesicles prepared above were applied (about 0.2 ml per tube) on the topof a sucrose step-gradient consisting of 3.5 ml of 15%, 30% and 45%(w/w) sucrose in isolation medium and centrifuged at 280,000 g_(max) for2 hours (SW 41 Ti rotor). After centrifugation the 30-45% sucroseinterfaces were collected, diluted approx. 20-fold in isolation mediumand pelletted at 100,000 g_(max) for 1 hour (SW 28 rotor). The pelletwas then resuspended in 1 ml of isolation medium, aliquoted and frozenin liquid N₂ and stored at −80° C. until used.

[0362] Human kidney membranes were obtained from the cortex of a humankidney, frozen immediately after surgery, according to the methodreported in the literature for bovine kidney (S. Gluck, J. Biol. Chem.,265, 21957 (1990)).

[0363] Proton transport in membrane vesicles was assessed,semi-quantitatively, by measuring the initial slope of fluorescencequench of acridine orange (excitation 490 nm; emission 530) afteraddition of 5-20 μl of membrane vesicles in 1 ml of buffer containing0.2 M sucrose, 50 mM KCl, 10 mM Hepes pH 7.4, 1 mM ATP.Na₂, 1 mM CDTA, 5μM valinomycin and 4 μM acridine orange. The reaction was started byaddition of 5 mM MgSO₄. Results were expressed as the percent of themean of two controls.

[0364] Inhibition of bafilomycin-sensitive ATPase activity was assessedin purified membrane vesicles by measuring the release of inorganicphosphate (Pi) during 30 min of incubation at 37° C. in a 96-well plateeither in the presence or in the absence of bafilomycin A1. The reactionmedium contained 1 mM ATP, 10 mM HEPES-Tris pH 8, 50 mM KCl, 5 uMvalinomycin, 5 uM nigericin, 1 mM CDTA-Tris, 100 uM ammonium molybdate,0.2 M sucrose and membranes (20 ug protein/ml). The reaction wasinitiated by MgSO₄ (8-arm pipette) and stopped, after 30 min, byaddition of 4 volumes of the malachite green reagent (96-arm pipette)prepared according to Chan [Anal. Biochem. 157, 375 (1986)]. Absorbanceat 650 nm was measured after 2 min using a microplate reader. Resultsare expressed as μmol (Pi)×mg protein⁻¹×hour⁻¹ and, for each experiment,represent the mean±sem of triplicates.

[0365] Pharmacological Data:

[0366] Inhibition of Bafilomycin-Sensitive ATPase in Chicken Osteoclasts

[0367] The compounds of the present invention are able to inhibitbafilomycin-sensitive ATPase in chicken osteoclast in a range from 18 nMto 1000 nM. In particular: Ex. No IC₅₀ (nM) ATPase assay 1 24 55 23 5924 61 41 62 30 64 67 68 18 74 42 75 30

[0368] Inhibition of Bone Resorption

[0369] In vitro Assays

[0370] 1) Bone resorption by disaggregated rat osteoclasts can beassessed as described previously in the literature [T. J. Chambers etal., Endocrinology, 1985, 116, 234]. Briefly, osteoclasts weremechanically disaggregated from neonatal rat long bones intoHepes-buffered medium 199 (Flow, UK). The suspension was agitated with apipette, and the larger fragments were allowed to settle for 30 sec. Thecells were then added to two wells of a multiwell dish containing boneslices (each measuring 12 mm²). After 15 min at 37° C. the bone sliceswere removed, washed in medium 199 and placed in individual wells of a96-well plate. These were incubated for 24 hrs in a total volume of 2 mlof culture medium, consisting of 10% foetal calf serum in Hanks-bufferedMEM, in the presence or absence of drug. The number of osteoclasts andbone resorption were quantified by confocal laser scanning microscopy(CLSM): the bone slices were fixed with 2% glutaraldehyde in 0.2 Mcacodylate buffer and the osteoclasts on each bone slice were stainedfor tartrate-resistant acid phosphatase. After counting the number oflarge, multinucleated, red-stained cells, the bone slices were immersedin 10% sodium hypochlorite for 5 min to remove cells, washed indistilled water and sputter-coated with gold. The entire surface of eachbone slice was then examined in CLSM. The number and the size of theosteoclastic excavations, the plain area and the volume of bone resorbedwas recorded. Results were expressed as mean pit number per bone slice,mean pit number per osteoclast, mean area per osteoclast or mean volumeper osteoclast.

[0371] 2) Bone resorption by human osteoclasts can be assessed using amodification of the method above. Briefly, human osteoclasts arepurified from human giant cell tumours by negative selection using PanHuman HLA II antibodies in conjunction with Dynal magnetic beads.Osteoclasts are seeded onto bovine bone slices in Hepes-buffered medium199 (Flow, UK). After 30 minutes, the bone slices are transferred into a24-well multi-plate (4 slices per well) containing 2 ml/well of medium,consisting of 10% foetal calf serum in D-MEM. One hour later, vehicle(DMSO) or test compounds at different concentrations in DMSO were addedand incubation was continued for 47 hours. Bone slices were then treatedand analysed as described above for the rat osteoclast assay.

[0372] 3) Inhibition of PTH-stimulated ⁴⁵Ca²⁺ release from pre-labelledfoetal rat long bone. The assay is based on that described by Raisz (J.Clin. Invest. 44:103-116, 1965). Time-mated Sprague-Dawley rats wereinjected subcutaneously with 200 mCi of ⁴⁵CaCl2 on the 18th day ofgestation. On the following day, the foetuses were removed asepticallyand the radii and ulnae were dissected free of adjacent soft tissue andthe cartilaginous ends, and then cultured for 24 hr at 37° C. in BGJmedium containing 1 mg/ml BSA. The bones were then transferred to freshmedium containing the test compounds (0.1-50 μM) with and without PTH(12 nM) and were incubated for an additional 48 hr. The media werecollected and the bones extracted to determine the mean % calciumrelease by scintillation counting. Results were expressed as the %inhibition compared to the amount of calcium released from culturesincubated with PTH alone

[0373] In vivo Assays

[0374] Prevention of retinoid-induced hypercalcaemia. The method usedwas that described by Trechsel et al., (J. Clin. Invest. 80:1679-1686,1987). Briefly, male Sprague-Dawley rats weighing 160-200 g (10 pergroup) were thyroparathyroidectomised and were treated subcutaneouslywith the retinoid Ro 13-6298 (30 μg/day) for three days and this wasfound to significantly increase blood serum calcium by 4-5 mg/100 ml.For inhibition of this effect, rats were treated simultaneously withtest compounds i.v. or p.o. at 0.1-100 mg/kg, or vehicle and bloodcalcium was measured as described above, before treatment and one dayafter the last administration. Results were expressed as % inhibitionwith respect to vehicle-treated animals.

[0375] Prevention of bone loss in osteoporosis induced by ovariectomyand immobilisation. Seven groups of 10 Sprague-Dawley rats (200 g)underwent ovariectomy plus neurectomy of the sciatic nerve in the righthind limb, while one group was sham-operated according to the methoddescribed by Hayashi et al., (Bone 10:25-28, 1989). It was demonstratedthat a steady-state was attained in the amount of trabecular bone lost6-12 weeks after the operations. During a 6-week period, the operatedanimals received the test compounds (0.1-100 mg/kg p.o. u.i.d.), orvehicle. At the end of this treatment period, the animals weresacrificed and the tibia and femur of the hind limb removed. The tibiawet and dry weight were determined, and the density (displacement ofwater) and ashes content (total weight, calcium and phosphorous content)also measured. The femur were fixed in 10% formalin, de-mineralised in5% formic acid and the coronal midshaft and longitudinal section of thedistal metaphysis cut and stained with haematoxilin and eosin.Histomorphometric evaluation was made using a semi-automated imageanalyser (Immagini & Computer, Milan, Italy). In the distal metaphysis,the % trabecular bone area in the secondary spongiosa (which is thetrabecular bone 1 mm from the epiphyseal growth plate to about 4 mmtowards the midshaft giving a total area of 5 mm²) and the number oftrabeculae (according to Parfitt et al., J. Bone Min. Res. 2: 595,(1987)) were determined in all animals. In the midshaft, the medullary,cortical (CA) and total (TA) cross-sectional area was measured and thecortical index (CI) determined from the formula CI=CA/TA.

[0376] Prevention of bone loss in ovariectomised mature rats. Themethodology employed is based on that described by Wronsky et al. [J.Bone Min. Res., 6, 387 (1991)]. The bone loss, prevalently cancellous,occuring after the surgery is monitored by dual emission X-rayabsorptiometry (DEXA) measurements of bone mineral density (BMD) of longbones and by HPLC measurements of urinary levels of products of bonecollagen breakdown, such as the cross-link residues pyridinoline (PYD),deoxypyridinoline (DPD) and lysine glycosides, i.e.galactosyl-hydroxylysine (GHYL) and glucosyl-galactosyl-hydroxylysine(GGHYL). Groups of 7-10 female Sprague-Dawley rats, about 90 days oldand weighing 200-250 g are used. Rats are anesthetised by sodiumpentobarbital (35 mg/kg i.v.), laparotomy is performed and ovaries arebilaterally removed. Wounds are adequately disinfected and sutured. Agroup is sham operated. During a 4-week experimental period, theoperated animals receive test compounds in the appropiate vehicle(0.1-100 mg/kg p.o. u.i.d.) or vehicle alone. Twenty-four-hr urinesamples are collected for PYD, DPD, GHYL and GGHYL determinations beforeand 2, 4, 8, 11, 15, 18, 22 and 25 days after surgery. The aliquots ofurine are frozen and stored at −20° C. until HPLC analysis.

[0377] Before and at the end of the experimental period, the bonemetaphyseal mineral densities of left distal femur and proximal tibiawere evaluated in vivo using lightly anaesthetised animals. Results areexpressed as % of prevention of bone loss versus vehicle treatedanimals, using the following equation, where BMD indicates the bonemineral density at the end of the experimental period and is expressedas the percent of pre-ovariectomy baseline:${{Percent}\quad {prevention}} = {\frac{{{BMD}({treatment})} - {{BMD}({vehicle})}}{{{BMD}({sham})} - {{BMD}({vehicle})}} \times 100}$

[0378] Biological Data for Compound of Example 1 Human OsteoclastResorption Assay IC₅₀ = 3.4 nM Human Kidney ATPase assay IC₅₀ = 363 nMProtection of bone loss in ovariectomised mature 76% rats at 10 mg/kgp.o.

[0379] Other Therapeutic Utilities:

[0380] The activity of the compounds of the invention for the otherutilities mentioned herein may be determined by according to thefollowing methods which are incorprated herein:

[0381] 1. Antitumor activity may be determined according to the methodsdisclosed in published International Application, Publication number93/18652; in particular the screen employed, experimental details andbibliography of M. R. Boyd et al., Status of the NCI preclinicalantitumor drug discovery screen; principles and practices of Oncology,3, issue 10, October 1989, Lippincott.

[0382] 2. Antiviral activity may be assessed using the in vitro assaysreported by H. Ochiai et al., Antiviral Research, 27, 425-430 (1995) orby C. Serra et al., Pharmacol. Res., 29, 359 (1994). Anti-HIV activitycan be assessed as reported in the literature, for example by S.Velásquez et al., J. Med. Chem., 38, 1641-1649 (1995)

[0383] 3. Antiulcer activity may be assessed in vivo using the methodsreported in the literature, for example, as described by C. J. Pfeiffer,Peptic Ulcer, C. J. Pfeiffer Ed., Munksgaard Publ., Copenaghen, 1971. Invitro assays for inhibition of vacuolization induced by Helicobacterpylori are described, for example, by E. Papini et al., FEMS MicrobiolLett., 113, 155-160 (1993)

[0384] 4. Usefulness in treating Alzheimer's disease may be determinedusing models in vitro such as inhibition of amiloyd-β production asdescrided in the literature by J. Knops et al., J. Biol. Chem., 270,2419-2422 (1995) or by models in vivo: such as the transgenic mousemodel overexpressing human APP reported by D. Games et al., Nature, 373,523-527 (1995).

[0385] 5. Immunosuppressant activity can be assessed as reported in theliterature, for example by M.-K. Hu et al., J. Med. Chem., 38, 4164-4170(1995)

[0386] 6.Antilipidemic activity can be assessed as reported in theliterature, for example by E. A. L. Biessen et al., J. Med. Chem. 38,1846-1852 (1995). Antiatherosclerotic activity may be assessed by usinganimal models of atherosclerosis, such as the atherosclerotic rabbitmodel, which are reported in the literature, for example by R. J. Lee etal., J. Pharm. Exp. Ther., 184, 105-112 (1973).

[0387] 7. Angiostatic activity may be assessed using the methodsreported in the literature, for example as described by T. Ishii et al.,J. Antibiot., 48, 12 (1995).

1. A selective inhibitor of the biological activity of human osteoclastcells, providing that such an inhibitor does not include any specificExample disclosed in WO 96/21644.
 2. An inhibitor according to claim 1,which is selective for the vacuolar H⁺-ATPase located on the ruffledborder of human osteoclasts.
 3. An inhibitor according to claim 1 orclaim 2, which interacts specifically with the 16 kDa subunit or the 116kDa subunit of the vacuolar H⁺-ATPase located on the ruffled border ofhuman osteoclasts.
 4. A compound of formula (I):

or a salt thereof, or a solvate thereof, wherein: Ra represents a groupR₅ which is hydrogen, alkyl or optionally substituted aryl and Rbrepresents a moiety of formula (a):

wherein X represents a hydroxy or an alkoxy group wherein the alkylgroup may be substituted or unsubstituted or X represents a groupNR_(s)R_(t) wherein R_(s) and R_(t) each independently representhydrogen, alkyl, substituted alkyl, optionally substituted alkenyl,optionally substituted aryl, optionally substituted arylalkyl, anoptionally substituted heterocyclic group or an optionally substitutedheterocyclylalkyl group, or R_(s) and R_(t) together with the nitrogento which they are attached form a heterocyclic group; R₁ represents analkyl or a substituted or unsubstituted aryl group; and R₂, R₃ and R₄each independently represent hydrogen, alkyl, aryl or substituted arylR₆ and R₇ each independently represents hydrogen, hydroxy, amino,alkoxy, optionally substituted aryloxy, optionally substitutedbenzyloxy, alkylamino, dialkylamino, halo, trifluoromethyl,trifluoromethoxy, nitro, alkyl, carboxy, carbalkoxy, carbamoyl,alkylcarbamoyl, or R₆ and R₇ together represent methylenedioxy,carbonyldioxy or carbonyldiamino; and R₈ represents hydrogen, hydroxy,alkanoyl, alkyl, aminoalkyl, hydroxyalkyl, carboxyalkyl,carbalkoxyalkyl, carbamoyl or aminosulphonyl; providing that such aninhibitor does not include any specific Example disclosed in WO96/21644.
 5. A compound according to claim 4, wherein R₁ representsmethyl.
 6. A compound according to claim 4 or claim 5, wherein R₂, R₃and R₄ each independently represent hydrogen, alkyl or phenyl.
 7. Acompound according to any one of claims 4 to 6, wherein R₅ is hydrogen.8. A compound according to any one of claims 4 to 7, wherein R₆ and R₇are hydrogen, halo, trifluoromethyl and alkoxy.
 9. A compound accordingto any one of claims 4 to 8, wherein R₆ is 5-chloro and R₇ is 6-chloro.10. A compound according to any one of claims 4 to 9, wherein R₈represents hydrogen.
 11. A compound according to any one of claims 4 to10, wherein X represents N R_(s) R_(t).
 12. A compound according toclaim 11, wherein R_(s) and R_(t) each independently represent hydrogen,alkyl, substituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, optionally substituted arylalkyl, an optionallysubstituted heterocyclic group or an optionally substitutedheterocyclylalkyl group.
 13. A compound according to claims 11 or 12,wherein R_(s) and R_(t) together represent a heterocyclic group.
 14. Acompound according to claim 13, wherein R_(s) and R_(t) togetherrepresent is a moiety of formula (H1):

wherein Z₁ is N or CX₅ wherein X₅ is selected from hydrogen, alkyl,alkoxy, alkylcarbonyl, aryl, aryloxy or arylcarbonyl and Z₂, X₃ and X₄are each independently selected from hydrogen, alkyl, aryl, cyano,amino, heterocyclyloxy, alkoxy carbonylalkyloxy, carboxyalkyloxy,aminoalkyloxy, aminoalkylamino, aminoalkenylamino (especiallyaminomethyleneamino) and alkanoylamino.
 15. A compound according toclaim 13, wherein R_(s) and R_(t) together represent a group of formula(H2):

wherein X₆, X₇, X₈, X₉, X₁₀, X₁₁, X₁₂ and X₁₃ are each independentlyselected from hydrogen, hydroxy, alkyl, suitably C₁₋₆ alkyl, cycloalkyl(suitably spirocondensed), mono or poly hydroxyalkyl, alkoxyalkyl,hydroxy-alkoxyalkyl, alkanoyl, alkoxycarbonyl, aminoalkyl (optionallyalkylated or acylated at nitrogen); or one of X₆ with X₁₂ and X₈ withX₁₀ represents a C₂₋₄ alkylene chain and the remaining variables X₇,X₁₃, X₉ and X₁₁ each independently represent hydrogen, hydroxy, alkyl,suitably C₁₋₆ alkyl, cycloalkyl (suitably spirocondensed), mono or polyhydroxyalkyl, alkoxyalkyl, hydroxy-alkoxyalkyl, alkanoyl,alkoxycarbonyl, aminoalkyl (optionally alkylated or acylated atnitrogen); and X₁₄ represents hydrogen or lower alkyl, mono orpolyhydroxyalkyl, mono or diaminoalkyl, aminocarbonyl, alkyl,carboxyalkyl, carbalkoxyalkyl, aryl, heterocyclyl, acyl, carbamoyl,alkylamino(cyanimidoyl), aminoalkanoyl, hydroxyalkanoyl. X₆, X₇, X₁₂ andX₁₃ each represent hydrogen.
 16. A compound according to claim 15,wherein X₈, and X₉ each independently represent hydrogen or alkyl.
 17. Acompound according to claim 15, wherein X₁₀ and X₁₁ each independentlyrepresent hydrogen or alkyl.
 18. A compound according to claim 15,wherein X₁₄ represents alkyl
 19. A compound according to claim 15,wherein X₈, X₉, X₁₀ and X₁₁ each independently represent methyl and X₆,X₇, X₁₂ and X₁₃ each represent hydrogen.
 20. A compound according toclaim 1, wherein R₁ is C₁₋₆ alkyl, R₂, R₃, R₄ and R₈ are hydrogen, R₆ is5-halo, R₇ is 6-halo, and X is a moiety NR_(s)R_(t) wherein R_(t) ishydrogen and R_(s) is a moiety of formula (f) or a moiety (H1) or (H2).21. A compound according to claim 1, being selected from any one ofexamples 1 to 79; or a salt thereof, or a solvate thereof.
 22. Acompound according to claim 1, being selected from examples, 31, 32 34,35, 47, 51, 55, 56, 59, 68 and 74; or a salt thereof, or a solvatethereof.
 23. A process for the preparation of a compound of formula (I)or a salt thereof or a solvate thereof, which process comprises reactinga compound of formula (II):

wherein R₂, R₃, R₄, R₆, R₇ and R₈ are as defined in relation to formula(I), with a reagent capable of converting a moiety of formula

into a moiety of the above defined formula (a); and thereafter, asnecessary, carrying out one or more of the following reactions: (i)converting one compound of formula (I) into another compound of formula(I); (ii) removing any protecting group; (iii) preparing a salt or asolvate of the compound so formed. 24 A pharmaceutical compositioncomprising a selective inhibitor of the pharmacological activity ofhuman osteoclast cells according to claim 1, and a pharmaceuticallyacceptable carrier therefor.
 25. An inhibitor of a mammalian osteoclastsaccording to claim 1, for use as an active therapeutic substance. 26.The use of a selective inhibitor of the biological activity of humanosteoclast cells according to claim 1, for the manufacture of amedicament for the treatment and/or prophylaxis of diseases associatedwith over activity of osteoclasts in mammals.
 27. A method for thetreatment and/or prophylaxis of diseases associated with over activityof osteoclasts in mammals which method comprises the administration ofan effective non-toxic, pharmaceutically amount of a selective inhibitorof mammalian osteoclasts according to claim 1.